Compositions and methods for treating colitis

ABSTRACT

Disclosed herein are compositions and methods for treating colitis and other inflammatory bowel diseases, inter alia, indeterminate colitis, Crohn&#39;s disease, irritable bowel syndrome and ischemic colitis.

PRIORITY

This application claims the benefit of Provisional Application Ser. No.61/258,914 and Provisional Application Ser. No. 61/258,918 that wereboth filed on Nov. 6, 2009, the entirety of which applications areincorporated herein by reference.

FIELD OF THE DISCLOSURE

Disclosed herein are compositions and methods for treating colitis andother inflammatory bowel diseases, inter alia, ulcerative colitis,Crohn's disease, irritable bowel syndrome and ischemic colitis.

SUMMARY

Colitis is the term used to describe inflammation of the colon. Thereare a variety of causes of colitis including infections, poor bloodsupply, and autoimmune reactions. The wall of the colon has numerouslayers. There is a smooth muscle layer that wraps the outside and isresponsible for squeezing the undigested food through the length of thecolon. The inner layers, or mucosa, come into contact with the fluid andallow water and electrolyte absorption to help solidify the feces. Themucosal layer is where the colon inflammation occurs and is responsiblefor the symptoms of colitis.

There are two types of inflammatory bowel disease. The first, ulcerativecolitis, is thought to be an autoimmune illness in which the body'simmune system attacks the colon and causes inflammation. Ulcerativecolitis begins in the rectum and may gradually spread throughout thecolon. The signs and symptoms are generally abdominal pain and bloodybowel movements.

Crohn's disease is a second type of inflammatory bowel disease, and caninvolve any part of the digestive tract from the esophagus and stomachto both the small and large intestine. It often has skip lesions, thatis diseased areas are interspersed with healthy areas of tissue.

The inflammatory bowel diseases (IBDs), ulcerative colitis and Crohn'sdisease, are currently controlled by a combination of medications thatare used in a step-wise approach. Initially, anti-inflammatorymedications are used, and if these are less than successful, medicationsthat suppress the immune system can be added. In the most severe cases,surgery may be required to remove all or parts of the colon and smallintestine. Treatment for ischemic colitis is initially supportive, usingintravenous fluids to rest the bowel and prevent dehydration. Ifadequate blood supply to the bowel isn't restored, surgery may berequired to remove parts of the bowel that have lost blood supply.

The disclosed compositions and methods comprise compounds that canstabilize HIF-1α and HIF-2α, as well as other factors that are presentin the compromised, depleted or over taxed immune system of a subjectsuffering from colitis or other inflammatory bowel disease. As such, thecauses of colitis and colitis related diseases can be successfullytreated without the need for surgical intervention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the prevention of weight loss in mice with TNBS-inducedcolitis due to pre-treatment with a compound disclosed in Table VIII.The data represented by solid circles () represent control animalswithout induced colitis and pretreated with vehicle, solid squares (▪)represent control animals with TNBS-induced colitis and pre-treated withvehicle, solid triangles (▴) represent animals without induced colitisthat were pre-treated with 5 mg/kg of a compound disclosed in TableVIII, solid inverted triangles (▾) represent animals with TNBS-inducedcolitis that were pre-treated with 0.3 mg/kg of a compound disclosed inTable VIII, solid diamonds (♦) represent animals with TNBS-inducedcolitis that were pre-treated with 1 mg/kg of a compound disclosed inTable VIII, and open circles (◯) represent animals with TNBS-inducedcolitis that were pre-treated with 5 mg/kg of a compound disclosed inTable VIII.

FIG. 2 a depicts the percent colon length found in the followingtreatment groups: (A) healthy mice; (B) mice having TNBS-induced colitispre-treated with 5 mg/kg a compound disclosed in Table VIII one dayprior to disease induction; (C) mice having TNBS-induced colitispost-treated with 5 mg/kg a compound disclosed in Table VIII two dayspost disease induction; and (D) mice having TNBS-induced colitisreceiving only vehicle treatment.

FIG. 2 b depicts the disease activity scores for (A) healthy mice; (B)mice having TNBS-induced colitis pre-treated with 5 mg/kg a compounddisclosed in Table VIII one day prior to disease induction; (C) micehaving TNBS-induced colitis post-treated with 5 mg/kg a compounddisclosed in Table VIII two days post disease induction; and (D) micehaving TNBS-induced colitis receiving only vehicle treatment.

FIG. 2 c shows the mesenteric lymph node (MLN) total leukocyte count foranimals receiving vehicle (A), TNBS-induced colitis receiving onlyethanol vehicle (B), animals without TNBS-induced colitis receiving 10mg/kg a compound disclosed in Table VIII; and animals havingTNBS-induced colitis and receiving 10 mg/kg a compound disclosed inTable VIII.

FIG. 3 depicts the change in hematocrit levels for the various groups inthis study. Group A (healthy control) was not subjected to TNBS-inducedcolitis and only received pre-treatment with vehicle; Group B wassubjected to TNBS-induced colitis and only received pre-treatment withvehicle; Group C was not subjected to TNBS-induced colitis and receiveda pre-treatment of 5 mg/kg of a compound disclosed in Table VIII; GroupD was subjected to TNBS-induced colitis and received a pre-treatment of0.3 mg/kg of a compound disclosed in Table VIII; Group E was subjectedto TNBS-induced colitis and received a pre-treatment with 1 mg/kg of acompound disclosed in Table VIII; and Group F was subjected toTNBS-induced colitis and received a pre-treatment with 5 mg/kg of acompound disclosed in Table VIII.

DETAILED DISCLOSURE

In this specification and in the claims that follow, reference will bemade to a number of terms that shall be defined to have the followingmeanings:

Throughout this specification, unless the context requires otherwise,the word “comprise,” or variations such as “comprises” or “comprising,”will be understood to imply the inclusion of a stated integer or step orgroup of integers or steps but not the exclusion of any other integer orstep or group of integers or steps.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a carrier” includes mixtures of two or more such carriers,and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material can beadministered to an individual along with the relevant active compoundwithout causing clinically unacceptable biological effects orinteracting in a deleterious manner with any of the other components ofthe pharmaceutical composition in which it is contained. Ranges may beexpressed herein as from “about” one particular value, and/or to “about”another particular value. When such a range is expressed, another aspectincludes from the one particular value and/or to the other particularvalue. Similarly, when values are expressed as approximations, by use ofthe antecedent “about,” it will be understood that the particular valueforms another aspect. It will be further understood that the endpointsof each of the ranges are significant both in relation to the otherendpoint, and independently of the other endpoint.

A weight percent of a component, unless specifically stated to thecontrary, is based on the total weight of the formulation or compositionin which the component is included.

By “effective amount” as used herein means “an amount of one or more ofthe disclosed HIF-1α prolyl hydroxylase inhibitors, effective at dosagesand for periods of time necessary to achieve the desired or therapeuticresult.” An effective amount may vary according to factors known in theart, such as the disease state, age, sex, and weight of the human oranimal being treated. Although particular dosage regimes may bedescribed in examples herein, a person skilled in the art wouldappreciated that the dosage regime may be altered to provide optimumtherapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. In addition,the compositions of this disclosure can be administered as frequently asnecessary to achieve a therapeutic amount.

“Admixture” or “blend” is generally used herein means a physicalcombination of two or more different components

“Excipient” is used herein to include any other compound that may becontained in or combined with one or more of the disclosed inhibitorsthat is not a therapeutically or biologically active compound. As such,an excipient should be pharmaceutically or biologically acceptable orrelevant (for example, an excipient should generally be non-toxic to thesubject). “Excipient” includes a single such compound and is alsointended to include a plurality of excipients.

As used herein, by a “subject” is meant an individual. Thus, the“subject” can include domesticated animals (e.g., cats, dogs, etc.),livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratoryanimals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds.“Subject” can also include a mammal, such as a primate or a human.

By “prevent” or other forms of the word, such as “preventing” or“prevention,” is meant to stop a particular event or characteristic, tostabilize or delay the development or progression of a particular eventor characteristic, or to minimize the chances that a particular event orcharacteristic will occur. Prevent does not require comparison to acontrol as it is typically more absolute than, for example, reduce. Asused herein, something could be reduced but not prevented, but somethingthat is reduced could also be prevented. Likewise, something could beprevented but not reduced, but something that is prevented could also bereduced. It is understood that where reduce or prevent are used, unlessspecifically indicated otherwise, the use of the other word is alsoexpressly disclosed.

By “reduce” or other forms of the word, such as “reducing” or“reduction,” is meant lowering of an event or characteristic (e.g.,vascular leakage). It is understood that this is typically in relationto some standard or expected value, in other words it is relative, butthat it is not always necessary for the standard or relative value to bereferred to.

The term “Treat” or other forms of the word such as “treated” or“treatment” is used herein to mean that administration of a compound ofthe present invention mitigates a disease or a disorder in a host and/orreduces, inhibits, or eliminates a particular characteristic or eventassociated with a disorder (e.g., infection caused by a microorganism).Thus, the term “treatment” includes, preventing a disorder fromoccurring in a host, particularly when the host is predisposed toacquiring the disease, but has not yet been diagnosed with the disease;inhibiting the disorder; and/or alleviating or reversing the disorder.Insofar as the methods of the present invention are directed topreventing disorders, it is understood that the term “prevent” does notrequire that the disease state be completely thwarted. Rather, as usedherein, the term preventing refers to the ability of the skilled artisanto identify a population that is susceptible to disorders, such thatadministration of the compounds of the present invention may occur priorto onset of a disease. The term does not imply that the disease state becompletely avoided.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that when a value is disclosed, then“less than or equal to” the value, “greater than or equal to the value,”and possible ranges between values are also disclosed, as appropriatelyunderstood by the skilled artisan. For example, if the value “10” isdisclosed, then “less than or equal to 10” as well as “greater than orequal to 10” is also disclosed. It is also understood that throughoutthe application data are provided in a number of different formats andthat this data represent endpoints and starting points and ranges forany combination of the data points. For example, if a particular datapoint “10” and a particular data point “15” are disclosed, it isunderstood that greater than, greater than or equal to, less than, lessthan or equal to, and equal to 10 and 15 are considered disclosed aswell as between 10 and 15. It is also understood that each unit betweentwo particular units are also disclosed. For example, if 10 and 15 aredisclosed, then 11, 12, 13, and 14 are also disclosed. By“antimicrobial” is meant the ability to treat or control (e.g., reduce,prevent, inhibit, break-down, or eliminate) microorganism growth orsurvival at any concentration. Similarly, the terms “antibacterial,”“antiviral,” and “antifungal” respectively mean the ability to treat orcontrol (e.g., reduce, prevent, inhibit, break-down, or eliminate)bacterial, viral, and fungal growth or survival at any concentration.

The term “anion” is a type of ion and is included within the meaning ofthe term “ion”. An “anion” is any molecule, portion of a molecule (e.g.,zwitterion), cluster of molecules, molecular complex, moiety, or atomthat contains a net negative charge or that can be made to contain a netnegative charge. The term “anion precursor” is used herein tospecifically refer to a molecule that can be converted to an anion via achemical reaction (e.g., deprotonation).

The term “cation” is a type of ion and is included within the meaning ofthe term “ion”. A “cation” is any molecule, portion of a molecule (e.g.,zwitterion), cluster of molecules, molecular complex, moiety, or atom,that contains a net positive charge or that can be made to contain a netpositive charge. The term “cation precursor” is used herein tospecifically refer to a molecule that can be converted to a cation via achemical reaction (e.g., protonation or alkylation).

“Chemotherapeutic agent” is used herein to include any otherpharmaceutically active compound that can be used in conjunction withthe disclosed HIF-1α prolyl hydroxylase inhibitors, for example,cytotoxic drugs such as 6-hydroxymethylacylfulvene, cyclophosphamide,dacarbazine, carmustine, doxorubicin, and methotrexate. Otherchemotherapeutic agents also include anti-inflammatory drugs, i.e.,non-steroidal anti-inflammatory compounds such as aspirin.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer, diastereomer, and meso compound,and a mixture of isomers, such as a racemic or scalemic mixture.

The following chemical hierarchy is used throughout the specification todescribe and enable the scope of the present disclosure and toparticularly point out and distinctly claim the units which comprise thecompounds of the present disclosure, however, unless otherwisespecifically defined, the terms used herein are the same as those of theartisan of ordinary skill. The term “hydrocarbyl” stands for any carbonatom-based unit (organic molecule), said units optionally containing oneor more organic functional group, including inorganic atom comprisingsalts, inter alia, carboxylate salts, quaternary ammonium salts. Withinthe broad meaning of the term “hydrocarbyl” are the classes “acyclichydrocarbyl” and “cyclic hydrocarbyl” which terms are used to dividehydrocarbyl units into cyclic and non-cyclic classes.

As it relates to the following definitions, “cyclic hydrocarbyl” unitscan comprise only carbon atoms in the ring (carbocyclic and aryl rings)or can comprise one or more heteroatoms in the ring (heterocyclic andheteroaryl). For “carbocyclic” rings the lowest number of carbon atomsin a ring are 3 carbon atoms; cyclopropyl. For “aryl” rings the lowestnumber of carbon atoms in a ring are 6 carbon atoms; phenyl. For“heterocyclic” rings the lowest number of carbon atoms in a ring is 1carbon atom; diazirinyl. Ethylene oxide comprises 2 carbon atoms and isa C₂ heterocycle. For “heteroaryl” rings the lowest number of carbonatoms in a ring is 1 carbon atom; 1,2,3,4-tetrazolyl. The following is anon-limiting description of the terms “acyclic hydrocarbyl” and “cyclichydrocarbyl” as used herein.

A. Substituted and Unsubstituted Acyclic Hydrocarbyl:

-   -   For the purposes of the present disclosure the term “substituted        and unsubstituted acyclic hydrocarbyl” encompasses 3 categories        of units:

-   1) linear or branched alkyl, non-limiting examples of which include,    methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl    (C₄), sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄), and the like;    substituted linear or branched alkyl, non-limiting examples of which    includes, hydroxymethyl (C₁), chloromethyl (C₁), trifluoromethyl    (C₁), aminomethyl (C₁), 1-chloroethyl (C₂), 2-hydroxyethyl (C₂),    1,2-difluoroethyl (C₂), 3-carboxypropyl (C₃), and the like.

-   2) linear or branched alkenyl, non-limiting examples of which    include, ethenyl (C₂), 3-propenyl (C₃), 1-propenyl (also    2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),    buten-4-yl (C₄), and the like; substituted linear or branched    alkenyl, non-limiting examples of which include, 2-chloroethenyl    (also 2-chlorovinyl) (C₂), 4-hydroxybuten-1-yl (C₄),    7-hydroxy-7-methyloct-4-en-2-yl (C₉),    7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like.

-   3) linear or branched alkynyl, non-limiting examples of which    include, ethynyl (C₂), prop-2-ynyl (also propargyl) (C₃),    propyn-1-yl (C₃), and 2-methyl-hex-4-yn-1-yl (C₇); substituted    linear or branched alkynyl, non-limiting examples of which include,    5-hydroxy-5-methylhex-3-ynyl (C₇), 6-hydroxy-6-methylhept-3-yn-2-yl    (C₈), 5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like.

B. Substituted and Unsubstituted Cyclic Hydrocarbyl:

-   -   For the purposes of the present disclosure the term “substituted        and unsubstituted cyclic hydrocarbyl” encompasses 5 categories        of units:

-   1) The term “carbocyclic” is defined herein as “encompassing rings    comprising from 3 to 20 carbon atoms, wherein the atoms which    comprise said rings are limited to carbon atoms, and further each    ring can be independently substituted with one or more moieties    capable of replacing one or more hydrogen atoms.” The following are    non-limiting examples of “substituted and unsubstituted carbocyclic    rings” which encompass the following categories of units:    -   i) carbocyclic rings having a single substituted or        unsubstituted hydrocarbon ring, non-limiting examples of which        include, cyclopropyl (C₃), 2-methyl-cyclopropyl (C₃),        cyclopropenyl (C₃), cyclobutyl (C₄), 2,3-dihydroxycyclobutyl        (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),        cyclopentadienyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆),        cycloheptyl (C₇), cyclooctanyl (C₈), 2,5-dimethylcyclopentyl        (C₅), 3,5-dichlorocyclohexyl (C₆), 4-hydroxycyclohexyl (C₆), and        3,3,5-trimethylcyclohex-1-yl (C₆).    -   ii) carbocyclic rings having two or more substituted or        unsubstituted fused hydrocarbon rings, non-limiting examples of        which include, octahydropentalenyl (C₈), octahydro-1H-indenyl        (C₉), 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl (C₉), decalinyl        (C₁₀), decahydroazulenyl (C₁₀).    -   iii) carbocyclic rings which are substituted or unsubstituted        bicyclic hydrocarbon rings, non-limiting examples of which        include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl,        bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl,        bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

-   2) The term “aryl” is defined herein as “units encompassing at least    one phenyl or naphthyl ring and wherein there are no heteroaryl or    heterocyclic rings fused to the phenyl or naphthyl ring and further    each ring can be independently substituted with one or more moieties    capable of replacing one or more hydrogen atoms.” The following are    non-limiting examples of “substituted and unsubstituted aryl rings”    which encompass the following categories of units:    -   i) C₆ or C₁₀ substituted or unsubstituted aryl rings; phenyl and        naphthyl rings whether substituted or unsubstituted,        non-limiting examples of which include, phenyl (C₆),        naphthylen-1-yl (C₁₀), naphthylen-2-yl (C₁₀), 4-fluorophenyl        (C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆),        2-amino-4-fluorophenyl (C₆), 2-(N,N-diethylamino)phenyl (C₆),        2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆),        3-methoxyphenyl (C₆), 8-hydroxynaphthylen-2-yl (C₁₀),        4,5-dimethoxynaphthylen-1-yl (C₁₀), and 6-cyano-naphthylen-1-yl        (C₁₀).    -   ii) C₆ or C₁₀ aryl rings fused with 1 or 2 saturated rings        non-limiting examples of which include,        bicyclo[4.2.0]octa-1,3,5-trienyl (C₈), and indanyl (C₉).

-   3) The terms “heterocyclic” and/or “heterocycle” are defined herein    as “units comprising one or more rings having from 3 to 20 atoms    wherein at least one atom in at least one ring is a heteroatom    chosen from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of    N, O, and S, and wherein further the ring which comprises the    heteroatom is also not an aromatic ring.” The following are    non-limiting examples of “substituted and unsubstituted heterocyclic    rings” which encompass the following categories of units:    -   i) heterocyclic units having a single ring containing one or        more heteroatoms, non-limiting examples of which include,        diazirinyl (C₁), aziridinyl (C₂), urazolyl (C₂), azetidinyl        (C₃), pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl        (C₃), isoxazolinyl (C₃), thiazolidinyl (C₃), isothiazolinyl        (C₃), oxathiazolidinonyl (C₃), oxazolidinonyl (C₃), hydantoinyl        (C₃), tetrahydrofuranyl (C₄), pyrrolidinyl (C₄), morpholinyl        (C₄), piperazinyl (C₄), piperidinyl (C₄), dihydropyranyl (C₅),        tetrahydropyranyl (C₅), piperidin-2-onyl (valerolactam) (C₅),        2,3,4,5-tetrahydro-1H-azepinyl (C₆), 2,3-dihydro-1H-indole (C₈),        and 1,2,3,4-tetrahydro-quinoline (C₉).    -   ii) heterocyclic units having 2 or more rings one of which is a        heterocyclic ring, non-limiting examples of which include        hexahydro-1H-pyrrolizinyl (C₇),        3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl (C₇),        3a,4,5,6,7,7a-hexahydro-1H-indolyl (C₈),        1,2,3,4-tetrahydroquinolinyl (C₉), and        decahydro-1H-cycloocta[b]pyrrolyl (C₁₀).

-   4) The term “heteroaryl” is defined herein as “encompassing one or    more rings comprising from 5 to 20 atoms wherein at least one atom    in at least one ring is a heteroatom chosen from nitrogen (N),    oxygen (O), or sulfur (S), or mixtures of N, O, and S, and wherein    further at least one of the rings which comprises a heteroatom is an    aromatic ring.” The following are non-limiting examples of    “substituted and unsubstituted heterocyclic rings” which encompass    the following categories of units:    -   i) heteroaryl rings containing a single ring, non-limiting        examples of which include, 1,2,3,4-tetrazolyl (C₁),        [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), triazinyl (C₃),        thiazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl (C₃), isoxazolyl        (C₃), isothiazolyl (C₃), furanyl (C₄), thiopheneyl (C₄),        pyrimidinyl (C₄), 2-phenylpyrimidinyl (C₄), pyridinyl (C₅),        3-methylpyridinyl (C₅), and 4-dimethylaminopyridinyl (C₅).    -   ii) heteroaryl rings containing 2 or more fused rings one of        which is a heteroaryl ring, non-limiting examples of which        include: 7H-purinyl (C₅), 9H-purinyl (C₅), 6-amino-9H-purinyl        (C₅), 5H-pyrrolo[3,2-d]pyrimidinyl (C₆),        7H-pyrrolo[2,3-d]pyrimidinyl (C₆), pyrido[2,3-d]pyrimidinyl        (C₂), 2-phenylbenzo[d]thiazolyl (C₇), 1H-indolyl (C₈),        4,5,6,7-tetrahydro-1-H-indolyl (C₈), quinoxalinyl (C₈),        5-methylquinoxalinyl (C₈), quinazolinyl (C₈), quinolinyl (C₉),        8-hydroxy-quinolinyl (C₉), and isoquinolinyl (C₉).

-   5) C₁-C₆ tethered cyclic hydrocarbyl units (whether carbocyclic    units, C₆ or C₁₀ aryl units, heterocyclic units, or heteroaryl    units) which connected to another moiety, unit, or core of the    molecule by way of a C₁-C₆ alkylene unit. Non-limiting examples of    tethered cyclic hydrocarbyl units include benzyl C₁-(C₆) having the    formula:

-   -   wherein R^(a) is optionally one or more independently chosen        substitutions for hydrogen. Further examples include other aryl        units, inter alia, (2-hydroxyphenyl)hexyl C₆-(C₆);        naphthalen-2-ylmethyl C₁-(C₁₀), 4-fluorobenzyl C₁-(C₆),        2-(3-hydroxy-phenyl)ethyl C₂-(C₆), as well as substituted and        unsubstituted C₃-C₁₀ alkylenecarbocyclic units, for example,        cyclopropylmethyl C₁-(C₃), cyclopentylethyl C₂-(C₅),        cyclohexylmethyl C₁-(C₆). Included within this category are        substituted and unsubstituted C₁-C₁₀ alkylene-heteroaryl units,        for example a 2-picolyl C₁-(C₆) unit having the formula:

-   -   wherein R^(a) is the same as defined above. In addition, C₁-C₁₂        tethered cyclic hydrocarbyl units include C₁-C₁₀        alkyleneheterocyclic units and alkylene-heteroaryl units,        non-limiting examples of which include, aziridinylmethyl C₁-(C₂)        and oxazol-2-ylmethyl C₁-(C₃).

For the purposes of the present disclosure carbocyclic rings are from C₃to C₂₀; aryl rings are C₆ or C₁₀; heterocyclic rings are from C₁ to C₉;and heteroaryl rings are from C₁ to C₉.

For the purposes of the present disclosure, and to provide consistencyin defining the present disclosure, fused ring units, as well asspirocyclic rings, bicyclic rings and the like, which comprise a singleheteroatom will be characterized and referred to herein as beingencompassed by the cyclic family corresponding to the heteroatomcontaining ring, although the artisan can have alternativecharacterizations. For example, 1,2,3,4-tetrahydroquinoline having theformula:

is, for the purposes of the present disclosure, considered aheterocyclic unit. 6,7-Dihydro-5H-cyclopentapyrimidine having theformula:

is, for the purposes of the present disclosure, considered a heteroarylunit. When a fused ring unit contains heteroatoms in both a saturatedring (heterocyclic ring) and an aryl ring (heteroaryl ring), the arylring will predominate and determine the type of category to which thering is assigned herein for the purposes of describing the disclosure.For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present disclosure, considered a heteroarylunit.

The term “substituted” is used throughout the specification. The term“substituted” is applied to the units described herein as “substitutedunit or moiety is a hydrocarbyl unit or moiety, whether acyclic orcyclic, which has one or more hydrogen atoms replaced by a substituentor several substituents as defined herein below.” The units, whensubstituting for hydrogen atoms are capable of replacing one hydrogenatom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbylmoiety at a time. In addition, these substituents can replace twohydrogen atoms on two adjacent carbons to form said substituent, newmoiety, or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. Atwo hydrogen atom replacement includes carbonyl, oximino, and the like.A two hydrogen atom replacement from adjacent carbon atoms includesepoxy, and the like. Three hydrogen replacement includes cyano, and thelike. The term substituted is used throughout the present specificationto indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkylchain; can have one or more of the hydrogen atoms replaced by asubstituent. When a moiety is described as “substituted” any number ofthe hydrogen atoms can be replaced. For example, 4-hydroxyphenyl is a“substituted aromatic carbocyclic ring (aryl ring)”,(N,N-dimethyl-5-amino)octanyl is a “substituted C₈ linear alkyl unit,3-guanidinopropyl is a “substituted C₃ linear alkyl unit,” and2-carboxypyridinyl is a “substituted heteroaryl unit.”

The following are non-limiting examples of units which can substitutefor hydrogen atoms on a carbocyclic, aryl, heterocyclic, or heteroarylunit:

-   i) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched, or    C₃-C₁₂ cyclic alkyl; for example, methyl (C₁), chloromethyl (C₁),    trifluoromethyl (C₁), aminomethyl (C₁), ethyl (C₂), hydroxymethyl    1-chloroethyl (C₂), 2-hydroxyethyl (C₂), 1,2-difluoroethyl (C₂),    n-propyl (C₃), iso-propyl (C₃), 3-carboxypropyl (C₃), cyclopropyl    (C₃), 2-methyl-cyclopropyl (C₃), n-butyl (C₄), sec-butyl (C₄),    iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄),    2,3-dihydroxycyclobutyl (C₄), pentyl (C₅), cyclopentyl (C₅), hexyl    (C₆), and cyclohexyl (C₆), and the like;-   ii) substituted or unsubstituted C₂-C₁₂ linear, C₃-C₁₂ branched, or    C₃-C₁₂ cyclic alkenyl; for example, ethenyl (C₂), 2-chloroethenyl    (also 2-chlorovinyl) (C₂), 3-propenyl (C₃), 1-propenyl (also    2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),    buten-4-yl (C₄), 4-hydroxybuten-1-yl (C₄), cyclobutenyl (C₄),    cyclopentenyl (C₅), cyclopentadienyl (C₅), cyclohexenyl (C₆),    7-hydroxy-7-methyloct-4-en-2-yl (C₉), and    7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like;-   iii) substituted or unsubstituted C₂-C₁₂ linear or C₃-C₁₂ branched    alkynyl; for example, ethynyl (C₂), prop-2-ynyl (also propargyl)    (C₃), propyn-1-yl (C₃), 2-methyl-hex-4-yn-1-yl (C₇);    5-hydroxy-5-methylhex-3-ynyl (C₇), 6-hydroxy-6-methylhept-3-yn-2-yl    (C₈), 5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like;-   iv) substituted or unsubstituted C₆ or C₁₀ aryl; for example,    phenyl, 2-chlorophenyl, 3-hydroxyphenyl, 4-nitrophenyl,    2-fluoro-4-methylphenyl, 3,5-dinitrophenyl, 8-hydroxynaphth-1-yl,    6-sulfonylnapth-2-yl, and the like;-   v) substituted or unsubstituted C₁-C₉ heterocyclic; for example, as    defined further herein;-   vi) substituted or unsubstituted C₁-C₁₁ heteroaryl; for example, as    defined further herein;-   vii) halogen; for example, fluoro, chloro, bromo, and iodo;-   viii) —[C(R^(23a))(R^(23b))]_(x)OR¹⁰;    -   R¹⁰ is chosen from:    -   a) —H;    -   b) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   c) C₆ or C₁₀ substituted or unsubstituted aryl or alkylenearyl;    -   d) C₁-C₉ substituted or unsubstituted heterocyclic;    -   e) C₁-C₁₁ substituted or unsubstituted heteroaryl;-   ix) —[C(R^(23a))(R^(23b))]_(x)N(R^(11a))(R^(11b));    -   R^(11a) and R^(11b) are each independently chosen from:    -   a) —H;    -   b) —OR¹²;        -   R¹² is hydrogen or C₁-C₄ linear alkyl;    -   c) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   d) C₆ or C₁₀ substituted or unsubstituted aryl;    -   e) C₁-C₉ substituted or unsubstituted heterocyclic;    -   f) C₁-C₁₁ substituted or unsubstituted heteroaryl; or    -   g) R^(11a) and R^(11b) can be taken together to form a        substituted or unsubstituted ring having from 3 to 10 carbon        atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen,        and sulfur;-   x) —[C(R^(23a))(R^(23b))]_(x)C(O)R¹³;    -   R¹³ is:    -   a) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   b) —OR¹⁴;        -   R¹⁴ is hydrogen, substituted or unsubstituted C₁-C₄ linear            alkyl, C₆ or C₁₀ substituted or unsubstituted aryl, C₁-C₉            substituted or unsubstituted heterocyclic, C₁-C₁₁            substituted or unsubstituted heteroaryl;    -   c) —N(R^(15a))(R^(15b));        -   R^(15a) and R^(15b) are each independently hydrogen,            substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,            or C₃-C₁₂ cyclic alkyl; C₆ or C₁₀ substituted or            unsubstituted aryl; C₁-C₉ substituted or unsubstituted            heterocyclic; C₁-C₁₁ substituted or unsubstituted            heteroaryl; or R^(15a) and R^(15b) can be taken together to            form a substituted or unsubstituted ring having from 3 to 10            carbon atoms and from 0 to 3 heteroatoms chosen from oxygen,            nitrogen, and sulfur;-   xi) —[C(R^(23a))(R^(23b))]_(x)OC(O)R¹⁶;    -   R¹⁶ is:    -   a) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   b) —N(R^(17a))(R^(17b));        -   R^(17a) and R^(17b) are each independently hydrogen,            substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,            or C₃-C₁₂ cyclic alkyl; C₆ or C₁₀ substituted or            unsubstituted aryl; C₁-C₉ substituted or unsubstituted            heterocyclic; C₁-C₁₁ substituted or unsubstituted            heteroaryl; or R^(17a) and R^(17b) can be taken together to            form a substituted or unsubstituted ring having from 3 to 10            carbon atoms and from 0 to 3 heteroatoms chosen from oxygen,            nitrogen, and sulfur;-   xii) —[C(R^(23a))(R^(23b))]_(x)NR¹⁸C(O)R¹⁹;    -   R¹⁸ is:    -   a) —H; or    -   b) substituted or unsubstituted C₁-C₄ linear, C₃-C4 branched, or        C₃-C4 cyclic alkyl;    -   R¹⁹ is:    -   a) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   b) —N(R^(20a))(R^(20b));        -   R^(20a) and R^(20b) are each independently hydrogen,            substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,            or C₃-C₁₂ cyclic alkyl; C₆ or C₁₀ substituted or            unsubstituted aryl; C₁-C₉ substituted or unsubstituted            heterocyclic; C₁-C₁₁ substituted or unsubstituted            heteroaryl; or R^(20a) and R^(20b) can be taken together to            form a substituted or unsubstituted ring having from 3 to 10            carbon atoms and from 0 to 3 heteroatoms chosen from oxygen,            nitrogen, and sulfur;-   xiii) —[C(R^(23a))(R^(23b))]_(x)CN;-   xiv) —[C(R^(23a))(R^(23b))]_(x)NO₂;-   xv) —[C(R^(23a))(R^(23b))]_(x)R²¹;    -   R²¹ is C₁-C₁₀ linear, C₃-C₁₀ branched, or C₃-C₁₀ cyclic alkyl        substituted by from 1 to 21 halogen atoms chosen from —F, —Cl,        —Br, or —I;-   xvi) —[C(R^(23a))(R^(23b))]_(x)SO₂R²²;    -   R²² is hydrogen, hydroxyl, substituted or unsubstituted C₁-C₄        linear or C₃-C₄ branched alkyl; substituted or unsubstituted C₆,        C₁₀, or C₁₄ aryl; C₂-C₁₅ alkylenearyl; C₁-C₉ substituted or        unsubstituted heterocyclic; or C₁-C₁₁ substituted or        unsubstituted heteroaryl;-   R^(23a) and R^(23b) are each independently hydrogen or C₁-C₄ alkyl;    and-   the index x is an integer from 0 to 5.

The compounds disclosed herein include all salt forms, for example,salts of both basic groups, inter alia, amines, as well as salts ofacidic groups, inter alia, carboxylic acids. The following arenon-limiting examples of anions that can form salts with basic groups:chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate,phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate,oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, andthe like. The following are non-limiting examples of cations that canform salts of acidic groups: sodium, lithium, potassium, calcium,magnesium, bismuth, and the like.

For the purposes of the present disclosure the terms “compound,”“analog,” and “composition of matter” stand equally well for one anotherand include all enantiomeric forms, diastereomeric forms, salts, and thelike, and the terms “compound,” “analog,” and “composition of matter.”

HIF-1α Prolyl Hydroxylase Inhibitors

The disclosed compounds have the following formulae:

wherein L is chosen from CH₂ or SO₂, thereby providing for N-substitutedbenzyl or N-substituted sulfonylaryl-3-hydroxypyridin-2-(1H)-ones. Y, R¹and R² are further defined herein below.

Disclosed herein are N-substituted benzyl and N-substitutedsulfonylaryl-4-aminomethylene-3-hydroxypyridin-2-(1H)-ones that areHIF-1α prolyl hydroxylase inhibitors having the formula:

wherein R¹ and R² are further defined herein below.

Alkyl Piperizine-1-Carboxylates

One category of these compounds relates to C₁-C₄ linear or branchedalkyl 4-{[(1-N-(chloro- orfluoro-substituted)-benzyl]-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methyl}piperazine-1-carboxylateshaving the formula:

wherein Z is a phenyl group that is substituted with from 1 to 5 halogenatoms that are chosen from chloro and fluoro, and R¹ and R² are takentogether to form a piperazine ring that is substituted with alkylcarboxyunit wherein R⁴ is chosen from C₁-C₄ linear or C₃-C₄ branched alkyl, forexample, tert butyl4{[1-(4chlorobenzyl)-3-hydroxy-2-oxo1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylatehaving the formula:

One aspect of R⁴ units relates to compounds wherein R⁴ is tert-butyl(C₄). Another aspect of R⁴ units relates to compounds wherein R⁴ ismethyl (C₁). A further aspect of R⁴ units relates to compounds whereinR⁴ is ethyl (C₂). A still further aspect of R⁴ units relates tocompounds wherein R⁴ is chosen from n-propyl (C₃), iso-propyl (C₃),n-butyl (C₄), sec-butyl (C₄), and iso-butyl (C₄). R⁴ is not hydrogen,therefore, a carboxylate unit having the formula: —CO₂H is expresslyexcluded from this category, but may be included in other categories asdescribed herein below.

Z is phenyl substituted with from 1 to 5 halogens chosen from fluorineand chlorine. One aspect of Z units relates to compounds wherein Z is4-chlorophenyl. Another aspect of Z units relates to compounds wherein Zis chosen from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl,3-fluorophenyl, or 4-fluorophenyl. A further aspect of Z units relatesto compounds wherein Z is chosen from 2,3-difluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, and2,6-dichlorophenyl.

The following are non-limiting examples of compounds according to thiscategory:

methyl4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

methyl4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

methyl4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

ethyl4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

ethyl4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

ethyl4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

tert-butyl4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

tert-butyl4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

tert-butyl4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

methyl4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

methyl4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

methyl4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

ethyl4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

ethyl4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

ethyl4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

tert-butyl4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

tert-Butyl4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatehaving the formula:

and

tert-butyl4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylatehaving the formula:

Another category of compounds relates toN-unsubstituted-benzyl-4-aminomethyl-3-hydroxypyridin-2-(1H)-ones,wherein Z is an unsubstituted phenyl group, having the formula:

wherein R¹ and R² are be taken together to form a substituted orunsubstituted heterocyclic or heteroaryl ring.

A first aspect of this category relates to compounds having the formula:

wherein R¹ and R² are be taken together to form a substituted orunsubstituted heterocyclic or heteroaryl ring represented by ring Ahaving from 2 to 20 carbon atoms and from 1 to 7 heteroatoms, and R²⁰⁰represents from 0 to 40 substitutions form hydrogen. The index w is aninteger from 0 to 40. Non-limiting examples of rings include diazirinyl(C₁), 1,2,3,4-tetrazolyl (C₁), aziridinyl (C₂), urazolyl (C₂),[1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), azetidinyl (C₃),pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃), isoxazolinyl(C₃), isoxazolyl (C₃), thiazolidinyl (C₃), isothiazolyl (C₃),isothiazolinyl (C₃), oxathiazolidinonyl (C₃), oxazolidinonyl (C₃),hydantoinyl (C₃), 1H-imidazolyl (C₃), pyrrolidinyl (C₄), morpholinyl(C₄), piperazinyl (C₄), piperidinyl (C₄), piperidin-2-onyl(valerolactam) (C₅), 7H-purinyl (C₅), 9H-purinyl (C₅),6-amino-9H-purinyl (C₅), 2,3,4,5-tetrahydro-1H-azepinyl (C₆),5H-pyrrolo[3,2-d]pyrimidinyl (C₆), 7H-pyrrolo[2,3-d]pyrimidinyl (C₆),and 1,2,3,4-tetrahydroquinoline (C₉).

Each R²⁰⁰ unit is independently chosen from:

-   i) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched, or    C₃-C₁₂ cyclic alkyl; for example, methyl (C₁), (C₁), chloromethyl    (C₁), trifluoromethyl (C₁), aminomethyl (C₁), ethyl (C₂),    hydroxymethyl 1-chloroethyl (C₂), 2-hydroxyethyl (C₂),    1,2-difluoroethyl (C₂), n-propyl (C₃), iso-propyl (C₃),    3-carboxypropyl (C₃), cyclopropyl (C₃), 2-methyl-cyclopropyl (C₃),    n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄),    cyclobutyl (C₄), 2,3-dihydroxycyclobutyl (C₄), pentyl (C₅),    cyclopentyl (C₅), hexyl (C₆), and cyclohexyl (C₆), and the like;-   ii) substituted or unsubstituted C₂-C₁₂ linear, C₃-C₁₂ branched, or    C₃-C₁₂ cyclic alkenyl; for example, ethenyl (C₂), 2-chloroethenyl    (also 2-chlorovinyl) (C₂), 3-propenyl (C₃), 1-propenyl (also    2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),    buten-4-yl (C₄), 4-hydroxybuten-1-yl (C₄), cyclobutenyl (C₄),    cyclopentenyl (C₅), cyclopentadienyl (C₅), cyclohexenyl (C₆),    7-hydroxy-7-methyloct-4-en-2-yl (C₉), and    7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like;-   iii) substituted or unsubstituted C₁-C₁₂ linear or C₃-C₁₂ branched    alkynyl; for example, ethynyl (C₂), prop-2-ynyl (also propargyl)    (C₃), propyn-1-yl (C₃), 2-methyl-hex-4-yn-1-yl (C₇);    5-hydroxy-5-methylhex-3-ynyl (C₇), 6-hydroxy-6-methylhept-3-yn-2-yl    (C₈), 5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like;-   iv) substituted or unsubstituted C₆ or C₁₀ aryl; for example, phenyl    (C₆), naphthylen-1-yl (C₁₀), naphthylen-2-yl (C₁₀), 4-fluorophenyl    (C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆),    2-amino-4-fluorophenyl (C₆), 2-(N,N-diethylamino)phenyl (C₆),    2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆), 3-methoxyphenyl    (C₆), 8-hydroxynaphthylen-2-yl (C₁₀), 4,5-dimethoxynaphthylen-1-yl    (C₁₀), 6-cyano-naphthylen-1-yl (C₁₀), and the like;-   v) substituted or unsubstituted C₁-C₉ heterocyclic; for example,    diazirinyl (C₁), aziridinyl (C₂), urazolyl (C₂), azetidinyl (C₃),    pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃),    isoxazolinyl (C₃), isoxazolyl (C₃), thiazolidinyl (C₃), isothiazolyl    (C₃), isothiazolinyl (C₃), oxathiazolidinonyl (C₃), oxazolidinonyl    (C₃), hydantoinyl (C₃), tetrahydropyranyl (C₄), pyrrolidinyl (C₄),    morpholinyl (C₄), piperazinyl (C₄), piperidinyl (C₄), dihydropyranyl    (C₅), tetrahydropyranyl (C₅), piperidin-2-onyl (valerolactam) (C₅),    and the like;-   vi) substituted or unsubstituted C₁-C₁₁ heteroaryl; for example,    1,2,3,4-tetrazolyl (C₁), [1,2,3]triazolyl (C₂), [1,2,4]triazolyl    (C₂), triazinyl (C₃), thiazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl    (C₃), furanyl (C₄), thiopheneyl (C₄), pyrimidinyl (C₄), pyridinyl    (C₅), and the like;-   vii) halogen; for example, —F, —Cl, —Br, or —I;-   viii) —[C(R^(37a))(R^(37b))]_(y)OR²⁴;    -   R²⁴ is chosen from:    -   a) —H;    -   b) substituted or unsubstituted C₂-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   c) substituted or unsubstituted C₆ or C₁₀ aryl or C₇ or C₁₀        alkylenearyl; for example, phenyl or benzyl    -   d) substituted or unsubstituted C₁-C₉ heterocyclic;    -   e) substituted or unsubstituted C₁-C₁₁ heteroaryl;        -   for example, —OH, —CH₂OH, —OCH₃, —CH₂OCH₃, —OCH₂CH₃,            —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and —CH₂OCH₂CH₂CH₃;-   ix) —[C(R^(37a))(R^(37b))]_(y)N(R^(25a))(R^(25b));    -   R^(25a) and R^(25b) are each independently chosen from:    -   a) —H;    -   b) —OR²⁶;        -   R²⁶ is hydrogen or C₁-C₄ linear alkyl;    -   c) substituted or unsubstituted C₂-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   d) substituted or unsubstituted C₆ or C₁₀ aryl;    -   e) substituted or unsubstituted C₁-C₉ heterocyclic;    -   f) substituted or unsubstituted C₁-C₁₁ heteroaryl; or    -   g) R^(25a) and R^(25b) can be taken together to form a        substituted or unsubstituted ring having from 3 to 10 carbon        atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen,        and sulfur;        -   for example, —NH₂, —CH₂NH₂, —NHCH₃, —N(CH₃)₂, —NHOH,            —NHOCH₃, —NH(CH₂CH₃), —CH₂NHCH₃, —CH₂N(CH₃)₂,            —CH₂NH(CH₂CH₃), and the like;-   x) —[C(R^(37a))(R^(37b))]_(y)C(O)R²⁷;    -   R²⁷ is:    -   a) substituted or unsubstituted C₂-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   b) —OR²⁸;        -   R²⁸ is hydrogen, substituted or unsubstituted C₁-C₄ linear            alkyl, substituted or unsubstituted C₆ or C₁₀ aryl,            substituted or unsubstituted C₁-C₉ heterocyclic, substituted            or unsubstituted C₁-C₁₁ heteroaryl;    -   c) —N(R^(29a))(R^(29b));        -   R^(29a) and R^(29b) are each independently hydrogen,            substituted or unsubstituted C₂-C₁₂ linear, C₃-C₁₂ branched,            or C₃-C₁₂ cyclic alkyl; substituted or unsubstituted C₆ or            C₁₀ aryl, substituted or unsubstituted C₁-C₉ heterocyclic,            substituted or unsubstituted C₁-C₁₁ heteroaryl; or R^(29a)            and R^(29b) can be taken together to form a substituted or            unsubstituted ring having from 3 to 10 carbon atoms and from            0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;        -   for example, —COCH₃, —CH₂COCH₃, —OCH₂CH₃, —CH₂COCH₂CH₃,            —COCH₂CH₂CH₃, —CH₂COCH₂CH₂CH₃, and the like;-   xi) —[C(R^(37a))(R^(37b))]_(y)OC(O)R³⁰;    -   R³⁰ is:    -   a) C₁-C₁₂ substituted or unsubstituted linear, branched, or        cyclic alkyl;    -   b) —N(R^(31a))(R^(31b));        -   R^(31a) and R^(31b) are each independently hydrogen,            substituted or unsubstituted C₂-C₁₂ linear, C₃-C₁₂ branched,            or C₃-C₁₂ cyclic alkyl; substituted or unsubstituted C₆ or            C₁₀ aryl, substituted or unsubstituted C₁-C₉ heterocyclic,            substituted or unsubstituted C₁-C₁₁ heteroaryl; or R^(31a)            and R^(31b) can be taken together to form a substituted or            unsubstituted ring having from 3 to 10 carbon atoms and from            0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;        -   for example, —OC(O)CH₃, —CH₂OC(O)CH₃, —OC(O)NH₂,            —CH₂OC(O)NH₂, —OC(O)NHCH₃, —CH₂OC(O)NHCH₃, —OC(O)N(CH₃)₂,            —CH₂OC(O)N(CH₃)₂, and the like;-   xii) —[C(R^(37a))(R^(37b))]_(y)NR³²C(O)R³³;    -   R³² is:    -   a) —H; or    -   b) substituted or unsubstituted C₁-C₄ linear, C₃-C₄ branched, or        C₃-C₄ cyclic alkyl;    -   R³³ is:    -   a) substituted or unsubstituted C₂-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   b) —N(R^(34a))(R^(34b));        -   R^(34a) and R^(34b) are each independently hydrogen,            substituted or unsubstituted C₂-C₁₂ linear, C₃-C₁₂ branched,            or C₃-C₁₂ cyclic alkyl; substituted or unsubstituted C₆ or            C₁₀ aryl, substituted or unsubstituted C₁-C₉ heterocyclic,            substituted or unsubstituted C₁-C₁₁ heteroaryl; C₁-C₁₁            substituted or unsubstituted heteroaryl; or R^(34a) and            R^(34b) can be taken together to form a substituted or            unsubstituted ring having from 3 to 10 carbon atoms and from            0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;        -   for example, —NHC(O)CH₃, —CH₂NHC(O)CH₃, —NHC(O)NH₂,            —CH₂NHC(O)NH₂, —NHC(O)NHCH₃, —CH₂NHC(O)NHCH₃, —OC(O)N(CH₃)₂,            —CH₂NHC(O)N(CH₃)₂, and the like;-   xiii) —[C(R^(37a))(R^(37b))]_(y)CN; for example; —CN, —CH₂CN, and    —CH₂CH₂CN;-   xiv) —[C(R^(37a))(R^(37b))]_(y)NO₂; for example; —NO₂, —CH₂NO₂, and    —CH₂CH₂NO₂;-   xv) —[C(R^(37a))(R^(37b))]_(y)R³⁵; for example, —CH₂F, —CHF₂, —CF₃,    —CCl₃, or —CBr₃;    -   R³⁵ is C₁-C₁₀ linear, C₃-C₁₀ branched, or C₃-C₁₀ cyclic alkyl        substituted by from 1 to 21 halogen atoms chosen from —F, —Cl,        —Br, or —I;-   xvi) —[C(R^(37a))(R^(37b))]_(y)SO₂R³⁶;    -   R³⁶ is hydrogen, hydroxyl, substituted or unsubstituted C₁-C₄        linear or C₃-C₄ branched alkyl; substituted or unsubstituted C₆,        C₁₀, or C₁₄ aryl; C₇-C₁₅ alkylenearyl; substituted or        unsubstituted C₁-C₉ heterocyclic; or substituted or        unsubstituted C₁-C₁₁ heteroaryl;    -   for example, —SO₂H, —CH₂SO₂H, —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and        —CH₂SO₂C₆H₅; and-   xv) two hydrogen atoms on a ring carbon atom can be substituted to    form a ═O, ═S, or ═NH unit;-   R^(37a) and R^(37b) are each independently hydrogen or C₁-C₄ alkyl;    and-   the index y is an integer from 0 to 5.

A first embodiment of this aspect relates to compounds wherein R¹ and R²are taken together to form a 5-member substituted or unsubstituted C₁-C₄heterocyclic or a substituted or unsubstituted C₁-C₄ heteroaryl ring,non-limiting examples of which include a ring chosen from:

A first iteration of this embodiment relates to HIF-1α prolylhydroxylase inhibitors having the formula:

R²⁰⁰ represents from 0 to 2 substitutions for a ring hydrogen, whereinthe substitutions for hydrogen are independently chosen from:

i) C₁-C₄ linear or C₃-C₄ branched alkyl;

ii) C₁-C₄ linear or C₃-C₄ branched alkoxy;

iii) hydroxyl;

iv) cyano;

v) nitro;

vi) amino, methylamino, or dimethylamino;

vii) carboxy, methyl carboxy; or ethyl carboxy;

viii) formyl, acetyl, or propionyl;

ix) amido, methyl amido, or dimethyl amido;

x) halogen;

xi) heterocyclic; or

xii) heteroaryl.

Non-limiting examples of this iteration include HIF-1α prolylhydroxylase inhibitors having the formula:

A further iteration of this embodiment relates to HIF-1α prolylhydroxylase inhibitors wherein R¹ and R² are taken together to form a5-member substituted or unsubstituted heterocyclic or heteroaryl ringhaving more than one heteroatom in the ring. Non-limiting examplesinclude:

Another embodiment of this aspect relates to HIF-1α prolyl hydroxylaseinhibitors wherein R¹ and R² are taken together to form a substituted orunsubstituted C₄-C₁₁ heterocyclic or a substituted or unsubstitutedC₄-C₁₁ heteroaryl ring, non-limiting examples of which are chosen from:

Non-limiting examples of this embodiment include:

Another category of compounds has the formula:

wherein R²⁰⁰ and the index w are the same as defined herein above. Rrepresents from 0 to 5 substitutions for hydrogen, wherein each R isindependently chosen from:

-   i) C₁-C₁₂ substituted or unsubstituted linear, branched, or cyclic    alkyl; for example, methyl (C₁), (C₁), chloromethyl (C₁),    trifluoromethyl (C₁), aminomethyl (C₁), ethyl (C₂), hydroxymethyl    1-chloroethyl (C₂), 2-hydroxyethyl (C₂), 1,2-difluoroethyl (C₂),    n-propyl (C₃), iso-propyl (C₃), 3-carboxypropyl (C₃), cyclopropyl    (C₃), 2-methyl-cyclopropyl (C₃), n-butyl (C₄), sec-butyl (C₄),    iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄),    2,3-dihydroxycyclobutyl (C₄), pentyl (C₅), cyclopentyl (C₅), hexyl    (C₆), and cyclohexyl (C₆), and the like;-   ii) C₂-C₁₂ substituted or unsubstituted linear, branched, or cyclic    alkenyl; for example, ethenyl (C₂), 2-chloroethenyl (also    2-chlorovinyl) (C₂), 3-propenyl (C₃), 1-propenyl (also    2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),    buten-4-yl (C₄), 4-hydroxybuten-1-yl (C₄), cyclobutenyl (C₄),    cyclopentenyl (C₅), cyclopentadienyl (C₅), cyclohexenyl (C₆),    7-hydroxy-7-methyloct-4-en-2-yl (C₉), and    7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like;-   iii) C₂-C₁₂ substituted or unsubstituted linear or branched alkynyl;    for example, ethynyl (C₂), prop-2-ynyl (also propargyl) (C₃),    propyn-1-yl (C₃), 2-methyl-hex-4-yn-1-yl (C₇);    5-hydroxy-5-methylhex-3-ynyl (C₇), 6-hydroxy-6-methylhept-3-yn-2-yl    (C₈), 5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like;-   iv) C₆ or C₁₀ substituted or unsubstituted aryl; for example, phenyl    (C₆), naphthylen-1-yl (C₁₀), naphthylen-2-yl (C₁₀), 4-fluorophenyl    (C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆),    2-amino-4-fluorophenyl (C₆), 2-(N,N-diethylamino)phenyl (C₆),    2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆), 3-methoxyphenyl    (C₆), 8-hydroxynaphthylen-2-yl (C₁₀), 4,5-dimethoxynaphthylen-1-yl    (C₁₀), 6-cyano-naphthylen-1-yl (C₁₀), and the like;-   v) C₁-C₉ substituted or unsubstituted heterocyclic; for example,    diazirinyl (C₁), aziridinyl (C₂), urazolyl (C₂), azetidinyl (C₃),    pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃),    isoxazolinyl (C₃), isoxazolyl (C₃), thiazolidinyl (C₃), isothiazolyl    (C₃), isothiazolinyl (C₃), oxathiazolidinonyl (C₃), oxazolidinonyl    (C₃), hydantoinyl (C₃), tetrahydropyranyl (C₄), pyrrolidinyl (C₄),    morpholinyl (C₄), piperazinyl (C₄), piperidinyl (C₄), dihydropyranyl    (C₅), tetrahydropyranyl (C₅), piperidin-2-onyl (valerolactam) (C₅),    and the like;-   vi) C₁-C₁₁ substituted or unsubstituted heteroaryl; for example,    1,2,3,4-tetrazolyl (C₁), [1,2,3]triazolyl (C₂), [1,2,4]triazolyl    (C₂), triazinyl (C₃), thiazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl    (C₃), furanyl (C₄), thiopheneyl (C₄), pyrimidinyl (C₄), pyridinyl    (C₅), and the like;-   vii) halogen; for example, —F, —Cl, —Br, or —I;-   viii) —[C(R^(23a))(R^(23b))]_(x)OR¹⁰;    -   R¹⁰ is chosen from:    -   a) —H;    -   b) C₁-C₁₂ substituted or unsubstituted linear, branched, or        cyclic alkyl;    -   c) C₆ or C₁₀ substituted or unsubstituted aryl or alkylenearyl;    -   d) C₁-C₉ substituted or unsubstituted heterocyclic;    -   e) C₁-C₁₁ substituted or unsubstituted heteroaryl;        -   for example, —OH, —CH₂OH, —OCH₃, —CH₂OCH₃, —OCH₂CH₃,            —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and —CH₂OCH₂CH₂CH₃;-   ix) —[C(R^(23a))(R^(23b))]_(x)N(R¹¹)(R^(11b));    -   R^(11a) and R^(11b) are each independently chosen from:    -   a) —H;    -   b) —OR¹²;        -   R¹² is hydrogen or C₁-C4 linear alkyl;    -   c) C₁-C₁₂ substituted or unsubstituted linear, branched, or        cyclic alkyl;    -   d) C₆ or C₁₀ substituted or unsubstituted aryl;    -   e) C₁-C₉ substituted or unsubstituted heterocyclic;    -   f) C₁-C₁₁ substituted or unsubstituted heteroaryl; or    -   g) R^(11a) and R^(11b) can be taken together to form a        substituted or unsubstituted ring having from 3 to 10 carbon        atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen,        and sulfur;        -   for example, —NH₂, —CH₂NH₂, —NHCH₃, —N(CH₃)₂, —NHOH,            —NHOCH₃, —NH(CH₂CH₃), —CH₂NHCH₃, —CH₂N(CH₃)₂,            —CH₂NH(CH₂CH₃), and the like;-   x) —[C(R^(23a))(R^(23b))]_(x)C(O)R¹³;    -   R¹³ is:    -   a) C₁-C₁₂ substituted or unsubstituted linear, branched, or        cyclic alkyl;    -   b) —OR¹⁴;        -   R¹⁴ is hydrogen, substituted or unsubstituted C₁-C₄ linear            alkyl, C₆ or C₁₀ substituted or unsubstituted aryl, C₁-C₉            substituted or unsubstituted heterocyclic, C₁-C₁₁            substituted or unsubstituted heteroaryl;    -   c) —N(R^(15a))(R^(15b));        -   R^(15a) and R^(15b) are each independently hydrogen, C₁-C₁₂            substituted or unsubstituted linear, branched, or cyclic            alkyl; C₆ or C₁₀ substituted or unsubstituted aryl; C₁-C₉            substituted or unsubstituted heterocyclic; C₁-C₁₁            substituted or unsubstituted heteroaryl; or R^(15a) and            R^(15b) can be taken together to form a substituted or            unsubstituted ring having from 3 to 10 carbon atoms and from            0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;        -   for example, —COCH₃, —CH₂COCH₃, —OCH₂CH₃, —CH₂COCH₂CH₃,            —COCH₂CH₂CH₃, —CH₂COCH₂CH₂CH₃, and the like;-   xi) —[C(R^(23a))(R^(23b))]_(x)OC(O)R¹⁶;    -   R¹⁶ is:    -   a) C₁-C₁₂ substituted or unsubstituted linear, branched, or        cyclic alkyl;    -   b) —N(R^(17a))(R^(17b));        -   R^(17a) and R^(17b) are each independently hydrogen, C₁-C₁₂            substituted or unsubstituted linear, branched, or cyclic            alkyl; C₆ or C₁₀ substituted or unsubstituted aryl; C₁-C₉            substituted or unsubstituted heterocyclic; C₁-C₁₁            substituted or unsubstituted heteroaryl; or R^(17a) and            R^(17b) can be taken together to form a substituted or            unsubstituted ring having from 3 to 10 carbon atoms and from            0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;-   xii) —[C(R^(23a))(R^(23b))]_(x)NR¹⁸C(O)R¹⁹;    -   R¹⁸ is:    -   a) —H; or    -   b) C₁-C₄ substituted or unsubstituted linear, branched, or        cyclic alkyl;    -   R¹⁹ is:    -   a) C₁-C₁₂ substituted or unsubstituted linear, branched, or        cyclic alkyl;    -   b) —N(R^(20a))(R^(20b));        -   R^(20a) and R^(20b) are each independently hydrogen, C₁-C₁₂            substituted or unsubstituted linear, branched, or cyclic            alkyl; C₆ or C₁₀ substituted or unsubstituted aryl; C₁-C₉            substituted or unsubstituted heterocyclic; C₁-C₁₁            substituted or unsubstituted heteroaryl; or R^(20a) and            R^(20b) can be taken together to form a substituted or            unsubstituted ring having from 3 to 10 carbon atoms and from            0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;        -   for example, —NHC(O)CH₃, —CH₂NHC(O)CH₃, —NHC(O)NH₂,            —CH₂NHC(O)NH₂, —NHC(O)NHCH₃, —CH₂NHC(O)NHCH₃, —OC(O)N(CH₃)₂,            —CH₂NHC(O)N(CH₃)₂, and the like;-   xiii) —[C(R^(23a))(R^(23b))]_(x)CN; for example; —CN, —CH₂CN, and    —CH₂CH₂CN;-   xiv) —[C(R^(23a))(R^(23b))]_(x)NO₂; for example; —NO₂, —CH₂NO₂, and    —CH₂CH₂NO₂;-   xv) —[C(R^(23a))(R^(23b))]_(x)R²¹; for example, —CH₂F, —CHF₂, —CF₃,    —CCl₃, or —CBr₃;    -   R²¹ is C₁-C₁₀ linear, branched, or cyclic alkyl substituted by        from 1 to 21 halogen atoms chosen from —F, —Cl, —Br, or —I;-   xvi) —[C(R^(23a))(R^(23b))]_(x)SO₂R²²;    -   R²² is hydrogen, hydroxyl, substituted or unsubstituted C₁-C₄        linear or branched alkyl; substituted or unsubstituted C₆, C₁₀,        or C₁₄ aryl; C₇-C₁₅ alkylenearyl; C₁-C₉ substituted or        unsubstituted heterocyclic; or C₁-C₁₁ substituted or        unsubstituted heteroaryl; for example, —SO₂H, —CH₂SO₂H, —SO₂CH₃,        —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅;-   R^(23a) and R^(23b) are each independently hydrogen or C₁-C₄ alkyl;    and-   the index x is an integer from 0 to 5.

Non-limiting examples of this category include compounds having theformula:

A further category of compounds relates to unsubstitutedN-benzyl-4-aminomethyl-3-hydroxypyridin-2-(1H)-ones having the formula:

wherein R¹ and R² are each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₁₀ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted C₂-C₁₀ linear, branched, or cyclicalkenyl;

iv) substituted or unsubstituted C₂-C₁₀ linear or branched alkynyl;

v) substituted or unsubstituted C₆ or C₁₀ aryl;

vi) substituted or unsubstituted C₁-C₉ heterocyclic; or

vii) substituted or unsubstituted C₁-C₉ heteroaryl.

The first aspect of this category relates to HIF-1α prolyl hydroxylaseinhibitors wherein R² is hydrogen and R¹ is substituted or unsubstitutedC₁-C₉ heterocyclic or C₁-C₉ heteroaryl. In a first embodiment, R¹ is asubstituted heterocyclic group, non-limiting examples of which includeaziridinyl (C₂), azetidinyl (C₃), pyrrolidinyl (C₄), morpholinyl (C₄),piperazinyl (C₄), piperidinyl (C₄), piperidin-2-onyl (valerolactam)(C₅), and azepan-2-only (caprolactam) (C₆), wherein the R¹ unit can bebonded to the nitrogen atom at any position in the ring. In addition,the C₁-C₉ heterocyclic or C₁-C₉ heteroaryl ring can be substituted atany position whether a ring carbon or a ring heteroatom, for example, aring nitrogen. Non-limiting examples of this embodiment include:

In another embodiment, R² is hydrogen and R¹ is substituted orunsubstituted C₃-C₁₂ cycloalkyl wherein the cycloalkyl ring can besubstituted at any ring position. Non-limiting examples of thisembodiment include:

A yet further category of compounds relates to unsubstitutedN-benzyl-4-aminomethyl-3-hydroxypyridin-2-(1H)-ones having the formula:

R¹ and R² are each independently hydrogen or substituted orunsubstituted C₁-C₁₀ linear or branched alkyl, wherein the alkyl unitcan be substituted by one or more units independently chosen from:

i) C₁-C₈ linear, branched, or cyclic alkoxy;

ii) hydroxy;

iii) halogen;

iv) cyano;

v) amino, C₁-C₈ mono-alkylamino, C₁-C₈ di-alkylamino;

vi) —SR⁴⁰; R⁴⁰ is hydrogen or C₁-C₄ linear or branched alkyl;

vii) substituted or unsubstituted C₆ of C₁₀ aryl;

viii) substituted or unsubstituted C₁-C₉ heterocyclic; or

ix) substituted or unsubstituted C₁-C₉ heteroaryl.

Non-limiting examples of this category include:

A still further category of the disclosed compounds has the formula:

wherein R²⁰⁰ and the index w are the same as defined herein above. Rrepresents from 0 to 5 substitutions for hydrogen, wherein each R isindependently chosen from:

-   i) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched, or    C₃-C₁₂ cyclic alkyl; for example, methyl (C₁), (C₁), chloromethyl    (C₁), trifluoromethyl (C₁), aminomethyl (C₁), ethyl (C₂),    hydroxymethyl 1-chloroethyl (C₂), 2-hydroxyethyl (C₂),    1,2-difluoroethyl (C₂), n-propyl (C₃), iso-propyl (C₃),    3-carboxypropyl (C₃), cyclopropyl (C₃), 2-methyl-cyclopropyl (C₃),    n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄),    cyclobutyl (C₄), 2,3-dihydroxycyclobutyl (C₄), pentyl (C₅),    cyclopentyl (C₅), hexyl (C₆), and cyclohexyl (C₆), and the like;-   ii) substituted or unsubstituted C₂-C₁₂ linear, C₃-C₁₂ branched, or    C₃-C₁₂ cyclic alkenyl; for example, ethenyl (C₂), 2-chloroethenyl    (also 2-chlorovinyl) (C₂), 3-propenyl (C₃), 1-propenyl (also    2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),    buten-4-yl (C₄), 4-hydroxybuten-1-yl (C₄), cyclobutenyl (C₄),    cyclopentenyl (C₅), cyclopentadienyl (C₅), cyclohexenyl (C₆),    7-hydroxy-7-methyloct-4-en-2-yl (C₉), and    7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like;-   iii) substituted or unsubstituted C₂-C₁₂ linear or C₃-C₁₂ branched    alkynyl; for example, ethynyl (C₂), prop-2-ynyl (also propargyl)    (C₃), propyn-1-yl (C₃), 2-methyl-hex-4-yn-1-yl (C₇);    5-hydroxy-5-methylhex-3-ynyl (C₇), 6-hydroxy-6-methylhept-3-yn-2-yl    (C₈), 5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like;-   iv) substituted or unsubstituted C₆ or C₁₀ aryl; for example, phenyl    (C₆), naphthylen-1-yl (C₁₀), naphthylen-2-yl (C₁₀), 4-fluorophenyl    (C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆),    2-amino-4-fluorophenyl (C₆), 2-(N,N-diethylamino)phenyl (C₆),    2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆), 3-methoxyphenyl    (C₆), 8-hydroxynaphthylen-2-yl (C₁₀), 4,5-dimethoxynaphthylen-1-yl    (C₁₀), 6-cyano-naphthylen-1-yl (C₁₀), and the like;-   v) substituted or unsubstituted C₁-C₉ heterocyclic; for example,    diazirinyl (C₁), aziridinyl (C₂), urazolyl (C₂), azetidinyl (C₃),    pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃),    isoxazolinyl (C₃), isoxazolyl (C₃), thiazolidinyl (C₃), isothiazolyl    (C₃), isothiazolinyl (C₃), oxathiazolidinonyl (C₃), oxazolidinonyl    (C₃), hydantoinyl (C₃), tetrahydropyranyl (C₄), pyrrolidinyl (C₄),    morpholinyl (C₄), piperazinyl (C₄), piperidinyl (C₄), dihydropyranyl    (C₅), tetrahydropyranyl (C₅), piperidin-2-onyl (valerolactam) (C₅),    and the like;-   vi) substituted or unsubstituted C₁-C₁₁ heteroaryl; for example,    1,2,3,4-tetrazolyl (C₁), [1,2,3]triazolyl (C₂), [1,2,4]triazolyl    (C₂), triazinyl (C₃), thiazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl    (C₃), furanyl (C₄), thiopheneyl (C₄), pyrimidinyl (C₄), pyridinyl    (C₅), and the like;-   vii) halogen; for example, —F, —Cl, —Br, or —I;-   viii) —[C(R^(23a))(R^(23b))]_(x)OR¹⁰;    -   R¹⁰ is chosen from:    -   a) —H;    -   b) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   c) substituted or unsubstituted C₆ or C₁₀ aryl or C₇ or C₁₀        alkylenearyl;    -   d) substituted or unsubstituted C₁-C₉ heterocyclic;    -   e) substituted or unsubstituted C₁-C₁₁ heteroaryl;        -   for example, —OH, —CH₂OH, —OCH₃, —CH₂OCH₃, —OCH₂CH₃,            —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and —CH₂OCH₂CH₂CH₃;        -   ix) —[C(R^(23a))(R^(23b))]_(x)N(R^(11a))(R^(11b));    -   R^(11a) and R^(11b) are each independently chosen from:    -   a) —H;    -   b) —OR¹²;        -   R¹² is hydrogen or C₁-C4 linear alkyl;    -   c) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   d) substituted or unsubstituted C₆ or C₁₀ aryl;    -   e) substituted or unsubstituted C₁-C₉ heterocyclic;    -   f) substituted or unsubstituted C₁-C₁₁ heteroaryl; or    -   g) R^(11a) and R^(11b) can be taken together to form a        substituted or unsubstituted ring having from 3 to 10 carbon        atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen,        and sulfur;        -   for example, —NH₂, —CH₂NH₂, —NHCH₃, —N(CH₃)₂, —NHOH,            —NHOCH₃, —NH(CH₂CH₃), —CH₂NHCH₃, —CH₂N(CH₃)₂,            —CH₂NH(CH₂CH₃), and the like;        -   x) —[C(R^(23a))(R^(23b))]_(x)C(O)R¹³;    -   R¹³ is:    -   a) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   b) —OR¹⁴;        -   R¹⁴ is hydrogen, substituted or unsubstituted C₁-C₄ linear            alkyl, substituted or unsubstituted C₆ or C₁₀ aryl,            substituted or unsubstituted C₁-C₉ heterocyclic, substituted            or unsubstituted C₁-C₁₁ heteroaryl;    -   c) —N(R^(15a))(R^(15b));        -   R^(15a) and R^(15b) are each independently hydrogen,            substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,            or C₃-C₁₂ cyclic alkyl; substituted or unsubstituted C₆ or            C₁₀ aryl; substituted or unsubstituted C₁-C₉ heterocyclic;            substituted or unsubstituted C₁-C₁₁ heteroaryl; or R^(15a)            and R^(15b) can be taken together to form a substituted or            unsubstituted ring having from 3 to 10 carbon atoms and from            0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;        -   for example, —COCH₃, —CH₂COCH₃, —OCH₂CH₃, —CH₂COCH₂CH₃,            —COCH₂CH₂CH₃, —CH₂COCH₂CH₂CH₃, and the like;        -   xi) —[C(R^(23a))(R^(23b))]_(x)OC(O)R¹⁶;    -   R¹⁶ is:    -   a) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   b) —N(R^(17a))(R^(17b));        -   R^(17a) and R^(17b) are each independently hydrogen,            substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,            or C₃-C₁₂ cyclic alkyl; substituted or unsubstituted C₆ or            C₁₀ aryl; substituted or unsubstituted C₁-C₉ heterocyclic;            substituted or unsubstituted C₁-C₁₁ heteroaryl; or R^(17a)            and R^(17b) can be taken together to form a substituted or            unsubstituted ring having from 3 to 10 carbon atoms and from            0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;        -   xii) —[C(R^(23a))(R^(23b))]_(x)NR¹⁸C(O)R¹⁹;    -   R¹⁸ is:    -   a) —H; or    -   b) substituted or unsubstituted C₁-C₄ linear, C₃-C₄ branched, or        C₃-C₄ cyclic alkyl;    -   R¹⁹ is:    -   a) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   b) —N(R^(20a))(R^(20b));        -   R^(20a) and R^(20b) are each independently hydrogen,            substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,            or C₃-C₁₂ cyclic alkyl; substituted or unsubstituted C₆ or            C₁₀ aryl; substituted or unsubstituted C₁-C₉ heterocyclic;            substituted or unsubstituted C₁-C₁₁ heteroaryl; or R^(20a)            and R^(20b) can be taken together to form a substituted or            unsubstituted ring having from 3 to 10 carbon atoms and from            0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;        -   for example, —NHC(O)CH₃, —CH₂NHC(O)CH₃, —NHC(O)NH₂,            —CH₂NHC(O)NH₂, —NHC(O)NHCH₃, —CH₂NHC(O)NHCH₃, —OC(O)N(CH₃)₂,            —CH₂NHC(O)N(CH₃)₂, and the like;-   xiii) —[C(R^(23a))(R^(23b))]_(x)CN; for example; —CN, —CH₂CN, and    —CH₂CH₂CN;-   xiv) —[C(R^(23a))(R^(23b))]_(x)NO₂; for example; —NO₂, —CH₂NO₂, and    —CH₂CH₂NO₂;-   xv) —[C(R^(23a))(R^(23b))]_(x)R²¹; for example, —CH₂F, —CHF₂, —CF₃,    —CCl₃, or —CBr₃;    -   R²¹ is C₁-C₁₀ linear, branched, or cyclic alkyl substituted by        from 1 to 21 halogen atoms chosen from —F, —Cl, —Br, or —I;        -   xvi) —[C(R^(23a))(R^(23b))]_(x)SO₂R²²;    -   R²² is hydrogen, hydroxyl, substituted or unsubstituted C₁-C₄        linear or C₃-C₄ branched alkyl; substituted or unsubstituted C₆,        C₁₀, or C₁₄ aryl; C₇-C₁₅ alkylenearyl; substituted or        unsubstituted C₁-C₉ heterocyclic; or substituted or        unsubstituted C₁-C₁₁ heteroaryl; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅;-   R^(23a) and R^(23b) are each independently hydrogen or C₁-C₄ alkyl;    and-   the index x is an integer from 0 to 5.

One aspect embodiment of this category relates to HIF-1α prolylhydroxylase inhibitors wherein R¹ and R² are taken together to form a5-member substituted or unsubstituted C₁-C₄ heterocyclic or asubstituted or unsubstituted C₁-C₄ heteroaryl ring, non-limitingexamples of which include a ring chosen from:

Another aspect of this category relates to HIF-1α prolyl hydroxylaseinhibitors wherein R¹ and R² are taken together to form a substituted orunsubstituted C₄-C₁₁ heterocyclic or a substituted or unsubstitutedC₄-C₁₁ heteroaryl ring, non-limiting examples of which are chosen from:

Non-limiting examples of this category include compounds having theformula:

A further category of the disclosed compounds has the formula:

wherein R represents from 1 to 5 optional substitutions for a phenylring hydrogen atom, R¹ and R² are each independently hydrogen orsubstituted or unsubstituted C₁-C₁₀ linear or branched alkyl, whereinthe alkyl unit can be substituted by one or more units independentlychosen from:

i) C₁-C₈ linear, C₃-C₈ branched, or C₃-C₈ cyclic alkoxy;

ii) hydroxy;

iii) halogen;

iv) cyano;

v) amino, C₁-C₈ mono-alkylamino, C₁-C₈ di-alkylamino;

vi) —SR⁴⁰; R⁴⁰ is hydrogen or C₁-C₄ linear or branched alkyl;

vii) substituted or unsubstituted C₆ of C₁₀ aryl;

viii) substituted or unsubstituted C₁-C₉ heterocyclic; or

ix) substituted or unsubstituted C₁-C₉ heteroaryl.

Non-limiting examples of this category include:

A still yet further category of the disclosed HIF-1α prolyl hydroxylaseinhibitors relates to compounds having the formula:

wherein R¹ and R² are taken together to form a substituted orunsubstituted piperazine ring, the substitutions on the ring as definedfor R²⁰⁰ herein above.

A yet still further category of the disclosed HIF-1α prolyl hydroxylaseinhibitors have the formula:

wherein R¹ and R² can be taken together to form a substituted orunsubstituted heterocyclic or heteroaryl ring having from 2 to 20 carbonatoms and from 1 to 7 heteroatoms wherein the rings formed exclude apiperazine ring.

Also disclosed herein are N-substituted benzyl or N-substitutedsulfonylaryl-3-hydroxypyridin-2-(1H)-ones having the formula:

that can be used to stimulate the cellular immune response in a subject.For these compounds, Z and L are the same as disclosed herein above.Non-limiting examples of these compounds include:

1-(4-chlorobenzyl)-3-hydroxypyridin-2(1H)-one having the formula:

1-(3-chlorobenzyl)-3-hydroxypyridin-2(1H)-one having the formula:

and

1-(2-chlorobenzyl)-3-hydroxypyridin-2(1H)-one having the formula:

Further disclosed herein are N-substituted benzyl or N-substitutedsulfonylaryl-5-substituted-3-hydroxypyridin-2-(1H)-ones having theformula:

wherein Y is substituted or unsubstituted phenyl, Z and L are the sameas defined herein above.

One aspect of Y relates to a phenyl group that is substituted with from1 to 5 halogen atoms, for example, Y is chosen from 2-chlorophenyl,3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl. Afurther aspect of Y units relates to compounds wherein Y is chosen from2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,2,6-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,2,5-dichlorophenyl, and 2,6-dichlorophenyl.

A non-limiting example of compounds according to this category include1-(4-chlorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one havingthe formula:

Further non-limiting examples include:

1-(2-chlorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(2-chlorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(2-chlorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-chlorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-chlorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-chlorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(4-chlorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(4-chlorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(2-fluorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(2-fluorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(2-fluorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-fluorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-fluorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-fluorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(4-fluorobenzyl)-5-(2-chlorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(4-fluorobenzyl)-5-(3-chlorophenyl)-3-hydroxypyridin-2(1H)-one

1-(4-fluorobenzyl)-5-(4-chlorophenyl)-3-hydroxypyridin-2(1H)-one

1-(2-chlorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(2-chlorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(2-chlorobenzyl)-5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-chlorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-chlorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-chlorobenzyl)-5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(4-chlorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(4-chlorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(4-chlorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one

1-(2-fluorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(2-fluorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(2-fluorobenzyl)-5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-fluorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-fluorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(3-fluorobenzyl)-5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(4-fluorobenzyl)-5-(2-fluorophenyl)-3-hydroxypyridin-2(1H)-one;

1-(4-fluorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one; and

1-(4-fluorobenzyl)-5-(3-fluorophenyl)-3-hydroxypyridin-2(1H)-one.

The disclosed compounds are organized into several categories for thestrictly non-limiting purpose of describing alternatives for syntheticstrategies for the preparation of subgenera of compounds within thescope of the disclosed compounds that are not expressly exemplifiedherein. This mental organization into categories does not imply anythingwith respect to increased or decreased biological efficacy with respectto any of the compounds or compositions of matter described herein.

Category I of the disclosed HIF-1α prolyl hydroxylase inhibitors relatesto compounds having the formula:

wherein A is a substituted or unsubstituted heterocyclic or heteroarylring having from 2 to 20 carbon atoms and from 1 to 7 heteroatoms, R²⁰⁰represents from 0 to 40 substitutions form hydrogen, R represents from 1to 5 substitutions for hydrogen as defined herein above, and the index nis from 1 to 5. Table I provides representative examples of compoundsaccording to this category.

TABLE I No. R A ring A1 3-methoxy pyrrolidin-1-yl A2 3-methoxy3-hydroxypyrrolidin-1-yl A3 3-methoxy 2-(pyrdin-2-yl)pyrrolidin-1-yl A43-methoxy 2-methylcarboxypyrrolidin-1-yl A5 3-methoxy2-(methoxymethyl)pyrrolidin-1-yl A6 3-methoxy thiazolidin-3-yl A73-methoxy 1H-imidazol-1-yl A8 3-methoxy piperidin-1-yl A9 3-methoxy4-benzylpiperidin-1-yl A10 3-methoxy 1,4′-bipiperidinyl-1′-yl A113-methoxy piperazin-1-yl A12 3-methoxy 4-benzylpiperazin-1-yl A133-methoxy 4-(2-methoxyphenyl)piperazin-1-ylmethyl A14 3-methoxy4-(6-chloropyridazin-3-yl)piperazin-1-yl A15 3-methoxy1,4-dioxa-8-azaspiro[4,5]dec-8-yl A16 3-methoxy morpholin-4-yl A173-methoxy thiomorpholin-4-yl A18 3-methoxy azepan-1-yl A19 3-methoxyazocan-1-yl A20 3-methoxy 3,4-dihydroquinolin-1(2H)-yl A21 4-chloropyrrolidin-1-yl A22 4-chloro 3-hydroxypyrrolidin-1-yl A23 4-chloro2-(pyrdin-2-yl)pyrrolidin-1-yl A24 4-chloro2-methylcarboxypyrrolidin-1-yl A25 4-chloro2-(methoxymethyl)pyrrolidin-1-yl A26 4-chloro thiazolidin-3-yl A274-chloro 1H-imidazol-1-yl A28 4-chloro piperidin-1-yl A29 4-chloro4-benzylpiperidin-1-yl A30 4-chloro 1,4′-bipiperidinyl-1′-yl A314-chloro piperazin-1-yl A32 4-chloro 4-benzylpiperazin-1-yl A33 4-chloro4-(2-methoxyphenyl)piperazin-1-ylmethyl A34 4-chloro4-(6-chloropyridazin-3-yl)piperazin-1-yl A35 4-chloro1,4-dioxB-8-azaspiro[4,5]dec-8-yl A36 4-chloro morpholin-4-yl A374-chloro thiomorpholin-4-yl A38 4-chloro azepan-1-yl A39 4-chloroazocan-1-yl A40 4-chloro 3,4-dihydroquinolin-1(2H)-yl A41 4-chloro4-tert-butoxycarbonylpiperazin-1-yl

The disclosed compounds of this category can be prepared by theprocedure outlined herein below in Scheme I and described in Example 1.

EXAMPLE 1tert-Butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate(4)

Preparation of 3-(tert-butyldimethylsilanyloxy)-1H-pyridin-2-one (1):3-Hydroxypyridin-2(1H)-one (15 g, 135 mmol) and imidazole (23 g, 338mmol) were suspended in dimethylformamide (200 mL) under inertatmosphere. A solution of tert-butyldimethylsilyl chloride (20.5 g, 136mmol) in dimethylformamide (200 mL) is added dropwise at roomtemperature over 30 minutes. The reaction was then allowed to stirovernight. The resulting solution was then poured into water (300 mL)and the mixture extracted with tert-butyl methyl ether (3×500 mL). Thecombined organic layer was washed with water (300 mL), brine (300 mL)then dried over Na₂SO₄. The solvent is removed under reduced pressureand the crude product crystallized from heptanes to afford 16.3 g (53%yield) of the desired product. ¹H NMR (250 MHz, CDCl₃) δ ppm 12.98 (1H,m); 6.91 (1H, dd, J=1.0 Hz, J=6.8 Hz); 6.81 (1H, dd, J=1.8 Hz, J=7.2Hz); 6.02-6.007 (1H, m); 0.90 (9H, s), and 0.17 (6H, s).

Preparation of3-(tert-butyldimethylsilanyloxy)-1-(3-chlorobenzyl)-1H-pyridin-2-one(2): At 0° C. under an inert atmosphere, a solution of 4-chlorobenzylchloride (4.44 mmol) in THF (10 mL) was added dropwise to a solution of3-(tert-butyldimethylsilanyloxy)-1H-pyridin-2-one, 1, (1 g, 4.44 mmol)and CsCO₃ (2.17 g, 6.66 mmol) in THF (10 mL). The reaction solution wasallowed to warm to room temperature and stirring was continuedovernight. The resulting solution was diluted with water (40 mL) andthen extracted with EtOAc (3×30 mL). The combined organic layer waswashed with brine (30 mL) then dried over Na₂SO₄. The solvent is removedunder reduced pressure and the crude product purified over silica(EtOAc:heptane 4:1) to afford the desired product as a white solid.

Preparation of 1-(4-chlorobenzyl)-3-hydroxypyridin-2(1H)-one (3): To asolution of3-(tert-butyldimethylsilanyloxy)-1-(3-chlorobenzyl)-1H-pyridin-2-one, 2,(2.36 g, 10 mmol) in EtOAc (25 mL) as added 5 M HCl (25 mL) withvigorous stirring at room temperature. The reaction was monitored by TLCfor the disappearance of starting material and was complete within 30minutes. The organic layer was decanted and the aqueous phase extractedwith dichloromethane (2×50 mL). The combined organic layers were driedover Na₂SO₄ and the solvent removed under reduced pressure. The crudeproduct was recrystallized from dichloromethane. The yield was nearlyquantitative. ¹H NMR (360 MHz, DMSO-d₆) δ ppm 5.12 (2H, s); 6.13 (1H, t,J=7.04); 6.71 (1H, dd, J=7.04, 1.59); 7.23-7.28 (2H, m); 7.36-7.43 (2H,m); 9.10 (1H, br. s).

Preparation oftert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate(4): tert-Butyl piperazine-1-carboxylate (97.6 mmol), formaldehyde (8 mLof a 37% soln., 97.6 mmol) and acetic acid (8 mL) were dissolved inethanol (350 mL) and the solution stirred for 1 hour at roomtemperature. A solution of1-(4-chlorobenzyl)-3-hydroxypyridin-2(1H)-one, 3, (48.8 mmol) in ethanol(350 mL) was added dropwise over 30 minutes. After 3 days of stirring,formaldehyde (3 mL) was added and the reaction heated to 50° C. afterwhich the reaction solution was concentrated under reduced pressure toapproximately 500 mL. The desired product is obtained by crystallizationfrom ethanol. ¹H NMR (250 MHz, CDCl₃) d ppm 1.46 (s, 9H); 2.38-2.57 (m,4H); 3.40-3.49 (m, 4H); 3.51 (s, 2H); 5.13 (s, 2H); 6.13 (d, J=7.16 Hz),1H); 6.79 (d, J=7.16 Hz, 1H); 7.20-7.41 (m, 4H); 8.33-8.85 (m, 1H). Thedisclosed biological data relate to A41.

Category II of the disclosed prolyl hydroxylase inhibitors relates tocompounds having the formula:

wherein A is a substituted or unsubstituted heterocyclic or heteroarylring having from 2 to 20 carbon atoms and from 1 to 7 heteroatoms, andR²⁰⁰ represents from 0 to 40 substitutions form hydrogen. Table IIprovides representative examples of compounds according to thiscategory.

TABLE II No. A ring B1 pyrrolidin-1-yl B2 3-hydroxypyrrolidin-1-yl B32-(pyrdin-2-yl)pyrrolidin-1-yl B4 2-methylcarboxypyrrolidin-1-yl B52-(methoxymethyl)pyrrolidin-1-yl B6 thiazolidin-3-yl B7 1H-imidazol-1-ylB8 piperidin-1-yl B9 4-benzylpiperidin-1-yl B10 1,4′-bipiperidinyl-1′-ylB11 piperazin-1-yl B12 4-benzylpiperazin-1-yl B134-(2-methoxyphenyl)piperazin-1-ylmethyl B144-(6-chloropyridazin-3-yl)piperazin-1-yl B151,4-dioxa-8-azaspiro[4,5]dec-8-yl B16 morpholin-4-yl B17thiomorpholin-4-yl B18 azepan-1-yl B19 azocan-1-yl B203,4-dihydroquinolin-1(2H)-yl

The compounds according to Category II can be prepared according to theprocedure outlined in Scheme I and disclosed in Example 1. The followingare further examples of inhibitors according to Category II.

1-Benzyl-3-hydroxy-4-(piperidin-1-ylmethyl)pyridin-2(1H)-one: ¹H NMR(300 MHz, CD₃OD) δ 1.81 (m, 6H), 3.07 (m, 2H), 3.51 (m, 2H), 4.23 (s,2H), 5.24 (s, 2H), 6.31 (d, J=6.9 Hz, 1H), 7.35 (m, 6H); ¹⁹F NMR (252MHz, CD₃OD) δ 85.5; 13C NMR (75 MHz, DMSO) δ 21.3, 22.7, 51.8, 52.5,53.1, 106.4, 117.4, 127.7, 128.0, 128.2, 128.9, 137.3, 147.4, 158.0; ESMS(M+1) 299.12; HRMS Calcd. For C₁₈H₂₂N₂O₂, 298.38. Found (M+1) 299.17.

1-Benzyl-3-hydroxy-4-(morpholin-4-ylmethyl)pyridin-2(1H)-one: ¹H NMR(300 MHz, DMSO) δ 3.25 (m, 4H), 3.81 (m, 4H), 4.18 (s, 2H), 5.17 (s,2H), 6.31 (d, J=6.9 Hz, 1H), 7.35 (m, 6H); ¹⁹FNMR (300 MHz, DMSO) δ88.5; ¹³C NMR (300 MHz, DMSO) δ 51.6, 51.8, 53.4, 63.5, 107.9, 119.1,127.8, 128.0, 128.2, 128.9, 137.3, 147.5, 158.3; ES MS(M+1) 301.12; HRMSCalcd. For C₁₇H₂₀N₂O₃, 300.35.

1-Benzyl-3-hydroxy-4-(thiomorpholin-4-ylmethyl)pyridin-2(1H)-one: ¹HNMR(300 MHz, DMSO) δ 2.92 (m, 4H), 3.38 (m, 4H), 4.17 (s, 2H), 5.16 (s,2H), 6.29 (d, J=7.5 Hz, 1H), 7.34 (m, 6H), 9.97 (s, 1H); ¹⁹F NMR (300MHz, DMSO) δ 88.4; ¹³C NMR (75 MHz, DMSO) δ 24.3, 51.9, 53.4, 53.7,107.9, 110.9, 127.8, 128.0, 128.2, 128.8, 137.2, 147.6, 157.6; ES MS(M+1) 317.14; HRMS Calcd. For C₁₇H₂₀N₂O₂S, 316.42. Found: (M+1) 317.13.

1-Benzyl-3-hydroxy-4-(thiazolidin-3-ylmethyl)pyridin-2(1H)-one: ¹HNMR(300 MHz, DMSO) δ 3.09 (t, J=6.3 Hz, 2H), 3.42 (t, J=6.3 Hz, 2H), 4.03(s, 2H), 4.29 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m,6H), 10.48 (broad s, 1H); ¹⁹FNMR (300 MHz, DMSO) δ 87.9; ¹³CNMR (75 MHz,DMSO) δ 28.3, 48.3, 50.1, 56.3, 57.0, 107.4, 122.1, 127.8, 128.2, 128.8,137.4, 146.3, 157.6; ES MS (M+1) 303.08; Anal. Calcd for C₁₈H₁₉N₂O₄SF,C, 51.92; H, 4.60; N, 6.73; S, 7.70. Found: C, 51.67; H, 4.48; N, 6.69;S, 7.65.

1-Benzyl-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridin-2(1H)-one: ¹H NMR(300 MHz, DMSO) δ 1.96 (s, 4H), 3.16 (s, 2H), 3.43 (s, 2H), 4.23 (s,4H), 5.17 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m, 6H); ¹⁹F NMR (252MHz, DMSO) δ 88.7; ¹³C NMR (75 MHz, DMSO) δ 22.8, 50.9, 51.8, 53.7,107.3, 118.0, 128.0, 128.2, 128.9, 137.3, 146.7, 157.6; ES MS (M+1)285.13; Anal. Calcd. For C₁₉H₂₁F₃N₂O₄, C, 57.28; H, 5.31; N, 7.03.Found: C, 57.10; H, 5.11, N, 7.02.

1-Benzyl-3-hydroxy-4-(4-benzylpiperidin-1-ylmethyl)pyridin-2(1H)-one: ¹HNMR (DMSO) δ 1.43 (m, 2H), 1.72 (m, 4H), 2.96 (m, 2H), 3.41 (m, 3H),4.09 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.35 (m, 11H); ¹⁹FNMR (252 MHz, DMSO) δ 88.8; ¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 389.21;HRMS Calcd. For C₂₅H₂₈N₂O₂, 388.50. Found (M+1) 389.22.

1-Benzyl-3-hydroxy-4-(4-benzylpiperazin-1-ylmethyl)pyridin-2(1H)-one: ¹HNMR (300 MHz, DMSO) δ 3.11 (broad s, 4H), 3.81 (s, 2H), 4.18 (s, 2H),5.15 (s, 2H), 6.24 (d, J=7.2 Hz, 1H), 7.34 (m, 6H), 7.46 (m, 5H); ¹⁹FNMR (252 MHz, DMSO) δ 88.2; 13C (75 MHz, DMSO) δ; ES MS(M+1) 390.21;HRMS Calcd. For C₂₄H₂₇N₃O₂, 389.49. Found (M+1) 390.21.

1-Benzyl-3-hydroxy-4-[(3-hydroxypyrrolidin-1-yl)methyl]pyridin-2(1H)-one:¹HNMR (300 MHz, DMSO) δ 1.90 (m, 1H), 3.18 (m, 2H), 3.47 (m, 3H), 4.24(s, 2H), 4.43 (s, 1H), 5.17 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m,6H); ¹⁹F NMR (252 MHz, DMSO) δ 89.0; ¹³C NMR (75 MHz, DMSO) δ 51.8,52.6, 61.3, 68.6, 107.4, 117.9, 128.0, 128.2, 128.9, 137.3, 146.7,157.6; ES MS(M+1) 301.13; HRMS Calcd. For C₁₇H₂₀N₂O₃, 300.35. Found:(M+1) 301.15.

1-Benzyl-3-hydroxy-4-(1,4-dioxa-8-azaspiro[4,5]dec-8-ylmethyl)pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 1.90 (m, 4H), 3.11 (m, 2H), 3.43 (m, 2H), 3.93(s, 4H), 4.19 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m,6H), 10.01 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.3; ¹³C NMR (75MHz, DMSO) δ 31.7, 50.7, 51.9, 52.5, 64.5, 101.1, 108.0, 116.5, 127.8,128.0, 128.3, 128.9, 137.3, 147.5 157.6; ES MS(M+1) 357.19; HRMS Calcd.For C₂₀H₂₄N₄O₂, 356.42. Found (M+1) 357.18.

1-Benzyl-3-hydroxy-4-azepan-1-ylmethylpyridin-2(1H)-one: ¹H NMR (300MHz, DMSO) δ 1.61 (m, 4H), 1.80 (m, 4H), 3.20 (m, 4H), 4.17 (s, 2H),5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m, 6H); ¹⁹F NMR (252 MHz,DMSO) δ 88.9; ¹³C NMR (75 MHz, DMSO) δ 22.8, 26.4, 51.8, 53.4, 54.4,107.6, 117.2, 127.9, 128.0, 18.2, 128.9, 137.3, 147.2, 157.6; ES MS(M+1)313.18; HRMS Calcd. For C₁₉H₂₄N₂O₄, 312.41. Found (M+1) 313.19.

1-Benzyl-3-hydroxy-4-(azocan-1-ylmethyl)pyridin-2(1H)-one: ¹H NMR (300MHz, DMSO) δ 1.59 (m, 10H), 3.18 (m, 2H), 3.38 (m, 2H), 4.17 (s, 2H),5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m, 6H); ¹⁹F NMR (252 MHz,DMSO) δ 88.9; ¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 327.2; HRMS Calcd.For C₂₀H₂₆N₂O₂, 326.43. Found (M+1) 327.20.

1-Benzyl-3-hydroxy-(1,4′-bipiperidinyl-1′-ylmethyl)pyridin-2(1H)-one: ¹HNMR (300 MHz, DMSO) δ 1.43-1.98 (m, 10H), 2.21 (m, 2H), 3.01 (m, 4H),3.43 (m, 3H), 4.12 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34(m, 6H), 9.85 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.7; ¹³C NMR (75MHz, DMSO) δ 21.6, 22.9, 23.8, 49.6, 50.5, 51.8, 53.0, 59.5, 108.0,127.8, 128.0, 128.2, 128.9, 137.3, 147.5, 157.6; ES MS(M+1) 382.4; HRMSCalcd. For C₂₃H₃₁N₃O₂, 383.51. Found (M+1) 382.25.

1-Benzyl-3-hydroxy-4-[(3,4-dihydroquinolin-1(2H)-yl)methyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 3.13 (t, J=6.3 Hz, 2H), 3.52 (m, 2H), 4.28 (s,2H), 4.41 (s, 2H), 5.18 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.23-7.41 (m,10H), 10.15 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.9; ¹³C NMR (75MHz, DMSO) δ 25.4; 49.3, 51.8, 52.7, 52.9, 107.6, 11.6, 116.8, 126.9,127.0, 127.9, 128.0, 128.1, 128.2, 128.8, 128.9, 131.7, 137.3, 147.3,157.6; ES MS(M+1) 347.40; HRMS Calcd. For C₂₂H₂₂N₂O₂, 346.42. Found(M+1) 347.17.

Methyl1-[(1-benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methyl]pyrrolidine-2-carboxylate:¹H NMR (300 MHz, DMSO) δ 2.01 (m, 3H), 2.45 (m, 1H), 3.26 (m, 1H), 3.53(m, 1H), 3.69 (s, 3H), 4.30 (m, 3H), 5.17 (s, 2H), 6.27 (d, 6.9 Hz, 1H),7.35 (m, 6H), ¹⁹F NMR (252 MHz, DMSO) δ 88.3; 13C NMR (75 MHz, DMSO) δ;ES MS(M+1) 343.20; HRMS Calcd. For C₁₉H₂₂N₂O₄, 342.39. Found (M+1)

1-Benzyl-3-hydroxy-4-{[2-(methoxymethyl)pyrrolidin-1-yl]methyl}pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 1.71 (m, 1H), 1.84 (m, 1H), 1.99 (m, 1H), 2.15(m, 1H), 3.19 (m, 1H), 3.30 (s, 3H), 3.41 (m, 1H), 3.62 (m, 2H), 3.77(m, 1H), 4.15 (m, 1H), 4.39 (m, 1H), 5.17 (s, 2H), 6.34 (d, J=7.2 Hz,1H), 7.34 (m, 6H); 9.60 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.3;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 329.2; HRMS Calcd. For C₁₉H₂₄N₂O₃,328.41. Found (M+1)

1-Benzyl-3-hydroxy-4-{[2-(pyrdin-2-yl)pyrrolidin-1-yl]methyl}pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 2.12 (m, 4H), 3.39 (m, 1H), 3.63 (m, 1H), 4.07(m, 2H), 4.60 (m, 1H), 5.10 (m, 2H), 6.15 (d, J=6.9 Hz, 1H), 7.33 (m,6H), 7.44 (m, 1H), 8.05 (d, J=8.1 Hz, 1H), 8.59 (d, J=4.8 Hz, 1H), 8.74(s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.0; ES MS(M+1) 362.22; HRMS Calcd.For C₂₂H₂₃N₃O₂, 361.44. Found (M+1).

1-Benzyl-3-hydroxy-4-[4-(6-chloropyridazin-3-yl)piperazin-1-ylmethyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 3.18 (m, 2H), 3.48 (m, 4H), 4.19 (s, 2H), 4.46(m, 2H), 5.16 (s, 2H), 6.62 (d, J=7.2 Hz, 1H), 7.35 (m, 6H), 7.48 (m,1H), 7.68 (m, 1H), 11.5 (broad s, 1H); ¹³C NMR (75 MHz, DMSO) δ 42.1,50.3, 51.9, 52.5, 108.2, 116.2; 118.0, 128.0, 128.2, 128.9, 129.8,137.3, 147.4, 157.6, 158.8; ES MS(M+1) 476.09. HRMS Calcd. ForC₂₁H₂₂ClN₅N₃O₂, 411.88. Found (M+1) 412.76.

1-Benzyl-3-hydroxy-4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 2.95 (m, 2H), 3.30 (m, 2H), 3.48 (m, 4H), 3.80(s, 3H), 4.25 (s, 2H), 5.18 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 6.93 (m,2H), 7.01 (m, 2H), 7.34 (m, 6H); ¹⁹F NMR (252 MHz, DMSO) δ 88.5; 13C NMR(75 MHz, DMSO) δ 47.2, 51.8, 53.0, 55.3, 108.1, 112.2, 114.8, 116.2,118.6, 121.2, 123.8, 127.8, 128.0, 128.9, 137.3, 139.6, 147.5, 152.2,157.6; ES MS(M+1) 405.82; HRMS Calcd. For C₂₄H₂₇N₃O₃, 405.49. Found(M+1) 406.21.

Category III of the disclosed prolyl hydroxylase inhibitors relates tocompounds having the formula:

R¹ and R² are each independently hydrogen or substituted orunsubstituted C₁-C₁₀ linear or branched alkyl, wherein the alkyl unitcan be substituted by one or more units independently chosen from:

i) C₁-C₈ linear, C₃-C₈ branched, or C₃-C₈ cyclic alkoxy;

ii) hydroxy;

iii) halogen;

iv) cyano;

v) amino, C₁-C₈ mono-alkylamino, C₁-C₈ di-alkylamino;

vi) —SR⁴⁰; R⁴⁰ is hydrogen or C₁-C₄ linear or C₃-C₄ branched alkyl;

vii) substituted or unsubstituted C₆ of C₁₀ aryl;

viii) substituted or unsubstituted C₁-C₉ heterocyclic; or

ix) substituted or unsubstituted C₁-C₉ heteroaryl.

Table III herein below provides non-limiting examples of compoundsencompassed by this category.

TABLE III No. R¹ R² C1 benzyl hydrogen C2 4-methoxybenzyl hydrogen C34-fluorobenzyl hydrogen C4 4-chlorobenzyl hydrogen C5 4-methylbenzylhydrogen C6 2-(pyridin-2-yl)ethyl hydrogen C7 [1,3]dioxolan-2-ylmethylhydrogen C8 tetrahydrofuran-2-ylmethyl hydrogen C9 2-methoxyethylhydrogen C10 1-hydroxy-2-methylpropan-2-yl hydrogen C11pyridin-4-ylmethyl hydrogen C12 furan-2-ylmethyl hydrogen C132-(methylthio)ethyl hydrogen C14 1-phenylethyl hydrogen C153-imidazol-1-ylpropyl hydrogen C16 cycloheptyl hydrogen C174-methylcyclohexyl hydrogen C18 1-benzylpiperidin-4-yl hydrogen C19azepan-2-on-3-yl hydrogen C20 1-benzylpyrrolidin-3-yl hydrogen C21benzyl methyl C22 4-methoxybenzyl methyl C23 4-fluorobenzyl methyl C244-chlorobenzyl methyl C25 4-methylbenzyl methyl C262-(pyridin-2-yl)ethyl methyl C27 [1,3]dioxolan-2-ylmethyl methyl C28tetrahydrofuran-2-ylmethyl methyl C29 2-methoxyethyl methyl C301-hydroxy-2-methylpropan-2-yl methyl C31 pyridin-4-ylmethyl methyl C32furan-2-ylmethyl methyl C33 2-(methylthio)ethyl methyl C34 1-phenylethylmethyl C35 3-(1H-imidazol-1-yl)propyl methyl C36 cycloheptyl methyl C374-methylcyclohexyl methyl C38 1-benzylpiperidin-4-yl methyl C39azepan-2-on-3-yl methyl C40 1-benzylpyrrolidin-3-yl methyl

The disclosed compounds of this category can be prepared by theprocedure outlined herein below in Scheme II and described in Example 2.

EXAMPLE 21-Benzyl-3-hydroxy-4-{[3-(1-H-imidazol-1-yl)propylamino]methyl}-pyridin-2(1H)-one(6)

N-Benzyl-3-hydroxypyridin-2(1H)-one (5) can be prepared according toExample 1 by substituting benzyl bromide or benzyl chloride into step(b) for (4-chloro)benzyl chloride.

1-Benzyl-3-hydroxy-4-{[3-(1-H-imidazol-1-yl)propylamino]methyl}pyridin-2(1H)-one(6): N-Benzyl-3-hydroxypyridin-2(1H)-one (5) (250 mg, 1.23 mmol) andformaldehyde (200 mg, 273 eq.) are combined in aqueous ethanol (10 mL)and stirred for 30 minutes. 3-(1-H-Imidazol-1-yl)propan-1-amine (340 mg,2 7 mmol) is then added and the reaction stirred for 12 hours. Thesolvent is removed by evaporation and the residue dissolved in methanol(2 mL) and purified via prep HPLC eluting with water/acetonitrile toafford the desired product as the trifluoroacetate salt. ¹H NMR (300MHz, DMSO) δ 2.19 (m, 2H), 2.97 (m, 2H), 4.02 (s, 2H), 4.30 (t, J=6.6Hz, 2H); 5.17 (s, 2H), 6.30 (d, J=6.9 Hz, 1H), 7.36 (m, 6H), 7.26 (s,1H), 7.76 (s, 1H), 9.03 (s, 1H), 9.11 (s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ88.5; ¹³C NMR (75 MHz, DMSO) δ 26.5, 44.0, 46.0, 51.8, 106.8, 118.7,120.5, 122.2, 127.9, 128.2, 128.9, 135.8, 137.4, 146.0, 158.2; ESMS(M+1) 339.05; HRMS Calcd. For C₁₉H₂₂N₄O₂, 338.44. Found (M+1) 339.18.

The following are further non-limiting examples of this aspect of thedisclosed HIF-1α prolyl hydroxylase inhibitors.

1-Benzyl-3-hydroxy-4-(benzylaminomethyl)pyridin-2(1H)-one: ¹HNMR (300MHz, DMSO) δ 4.01 (s, 2H), 4.20 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2Hz, 1H), 7.36 (m, 11H), 9.16 (broad s, 1H); ¹⁹FNMR (252 MHz, DMSO) δ88.6; ¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 321.16; Anal. Calcd. ForC₂₂H₂₁F₃N₂O₄, C, 60.83; H, 4.87; N, 6.45. Found: C, 60.75; H, 4.56; N,6.34.

1-Benzyl-3-hydroxy-4-{[(2-(pyridin-2-yl)ethylamino]methyl}pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 3.26 (m, 2H), 3.37 (m, 2H), 4.08 (s, 2H), 5.17(s, 2H); 6.34 (d, J=7.2 Hz, 1H), 7.38 (m, 6H), 7.86 (d, J=5.7 Hz, 2H),8.84 (m, 2H), 9.32 (broad s, 1H); ¹⁹FNMR (252 MHz, DMSO) δ 88.6; ¹³C NMR(75 MHz, DMSO) δ 31.5, 44.1, 46.3, 51.8, 106.9, 114.8, 127.1, 128.1,128.8, 137.4, 143.8, 146.1, 155.3, 157.5, 158.4; ES MS (M+1) 336.18;HRMS Calcd For C₂₀H₂₁N₃O₂, 335.40. Found: 336.16.

1-Benzyl-3-hydroxy-4-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 1.56 (m, 1H), 1.86 (m, 2H), 1.99 (m, 1H), 2.92(m, 1H), 3.05 (m, 1H), 3.80 (m, 2H), 4.09 (m, 3H), 5.16 (s, 2H), 6.34(d, J=7.2 Hz, 1H), 7.34 (m, 6H); 8.91 (broad s, 1H); ¹⁹F NMR (252 MHz,DMSO) δ 88.5; ¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 315.16; HRMS. Calcd.For C₁₈H₂₂N₂O₃, 314.38. Found (M+1) 315.16.

1-Benzyl-3-hydroxy-4-[(2-methoxyethylamino)methyl]pyridin-2(1H)-one: ¹HNMR (300 MHz, DMSO) δ 3.13 (broad s, 2H), 3.30 (s, 3H), 3.59 (t, J=5.4Hz, 2H), 4.02 (s, 2H), 5.16 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m,6H), 8.91 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.4; ¹³C NMR (252MHz, DMSO) δ; ES MS(M+1) 289.13; HRMS Calcd. For C₁₆H₂₀N₂O₃, 288.34.Found (M+1) 289.15.

1-Benzyl-3-hydroxy-4-[(1-hydroxy-2-methylpropan-2-ylamino)methyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 1.27 (s, 6H), 3.49 (s, 2H), 3.95 (s, 2H), 5.17(s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34 (m, 6H), 8.47 (broad s, 2H), 9.94(broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.7; 13C NMR (75 MHz, DMSO) δ;ES MS(M+1) 303.19; HRMS Calcd. For C₁₇H₂₂N₂O₃, 302.37. Found (M+1)303.17.

1-Benzyl-3-hydroxy-4-[(pyridin-4-ylmethylamino)methyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 4.07 (s, 2H), 4.32 (s, 2H), 5.16 (s, 2H), 6.34(d, J=7.2 Hz, 1H), 7.34 (m, 6H); 7.62 (d, J=5.7 Hz, 2H), 8.71 (d, J=4.5Hz, 2H); ¹⁹F NMR (252 MHz, DMSO) δ 88.0; ¹³C NMR (75 MHz, DMSO) δ; ESMS(M+1) 322.17; HRMS Calcd. For C₁₉H₁₉N₃O₂, 321.37. Found (M+1) 322.15.

1-Benzyl-3-hydroxy 4-{[(furan-2-ylmethyl)amino]methyl}pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 4.00 (s, 2H), 4.28 (s, 2H), 5.16 (s, 2H), 6.27(d, J=6.9 Hz, 1H), 6.54 (m, 1H), 6.65 (m, 1H), 7.34 (m, 6H), 7.80 (m,1H), 9.27 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.3; ¹³C NMR (75MHz, DMSO) δ; ES MS(M+1) 323.15; HRMS Calcd. For C₁₈H₁₈N₂O₃, 310.35.Found (M+1)

1-Benzyl-3-hydroxy-4-{[2-(methylthio)ethylamino]methyl}pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 2.10 (s, 3H), 2.74 (t, J=6.9 Hz, 2H), 3.16 (t,J=8.1 Hz, 2H), 4.05 (s, 2H), 5.17 (s, 2H), 6.34 (d, J=7.2 Hz, 1H), 7.34(m, 6H), ¹⁹F NMR (252 MHz, DMSO) δ 89.0; ES MS(M+1) 305.14, HRMS Calcd.For C₁₆H₂₀N₂O₂S, 304.41. Found (M+1)

1-Benzyl-3-hydroxy-4-[(4-methoxybenzylamino)methyl]pyridin-2(1H)-one: ¹HNMR (300 MHz, DMSO) δ 3.70 (s, 3H), 3.98 (s, 2H), 4.13 (s, 2H), 5.16 (s,2H), 6.28 (d, J=7.5 Hz, 1H), 7.00 (d, J=9.0 Hz, 4H), 7.34 (m, 6H); 9.07(broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 89.0; ES MS(M+1) 351.10; HRMSCalcd. For C₂₁H₂₂N₂O₃, 350.41. Found (M+1) 351.17.

1-Benzyl-3-hydroxy-4-[(1-phenylethylamino)methyl]pyridin-2(1H)-one: ¹HNMR (300 MHz, DMSO) δ 1.59 (d, J=7.2 Hz, 3H), 3.71-3.93 (m, 2H), 4.45(m, 1H), 5.15 (s, 2H), 6.28 (d, J=7.5 Hz, 1H), 7.34 (m, 11H); ¹⁹F NMR(252 MHz, DMSO) δ 88.9; ¹³C NMR (75 MHz, DMSO) δ 19.6, 42.5, 51.7, 58.0,106.8, 119.3, 128.0, 128.1, 128.2, 128.9, 129.3, 129.4, 137.3, 145.9,158.3; ES MS(M+1) 335.13; HRMS Calcd. For C₂₁H₂₂N₂O₂, 334.41. Found(M+1) 335.17.

1-Benzyl-3-hydroxy-4-(cycloheptylaminomethyl)pyridin-2(1H)-one: ¹H NMR(300 MHz, DMSO) δ 1.55 (m, 10H), 2.03 (m, 2H), 3.18 (s, 1H), 3.99 (m,2H), 5.17 (s, 2H), 6.32 (d, J=6.9 Hz, 1H), 7.35 (m, 6H), 8.65 (broad s,2H), 9.98 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.6; ¹³C NMR (75MHz, DMSO) δ 23.0, 27.2, 30.4, 41.6, 51.7, 58.9, 107.0, 111.7, 127.9,128.0, 128.2, 128.8, 137.4, 146.0, 157.5; ES MS(M+1) 327.13; HRMS Calcd.For C₂₀H₂₆N₂O₂, 326.43. Found (M+1) 327.20.

1-Benzyl-3-hydroxy-4-[(4-methylcyclohexylamino)methyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 0.93 (d, J=6.9 Hz, 3H), 1.38 (m, 4H),1.74 (m,4H), 2.05 (m, 1H), 3.10 (m, 1H), 4.01 (s, 2H), 5.17 (s, 2H), 6.31 (m,1H), 7.34 (m, 6H), 8.05 (broad s, 2H), 9.98 (broad s, 1H); ¹⁹F NMR (252MHz, DMSO) δ 88.9; ES MS(M+1) 327.14; HRMS Calcd. For C₂₀H₂₆N₂O₂,326.43; Found (M+1) 372.20.

1-Benzyl-3-hydroxy-4-[(1-benzylpiperidin-4-ylamino)methyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 1.77 (m, 2H), 2.31 (m, 2H), 2.98 (m, 2H), 3.30(m, 3H), 3.46 (m, 2H), 4.03 (s, 2H), 0.29 (s, 2H), 5.16 (s, 2H), 6.30(d, J=7.5 Hz, 1H), 7.34 (m, 6H), 7.49 (s, 5H), 9.12 (broad s, 1H), 10.05(broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.8; ¹³C NMR (75 MHz, DMSO) δ27.1, 43.4, 51.8, 52.1, 54.2, 54.7, 57.6, 106.9, 118.5, 128.0, 128.1,128.8, 129.3, 129.8, 130.7, 131.3, 137.3, 146.2, 157.4; ES MS(M+1)404.56; HRMS Calcd. For C₂₅H₂₈N₃O₂, 403.52. Found (M+1) 404.23.

3-[(1-Benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methylamino]azepan-2-one:¹H NMR (300 MHz, DMSO) δ 1.25 (m, 1H), 1.59 (m, 2H), 1.74 (m, 1H), 1.92(m, 1H), 2.10 (m, 1H), 3.18 (m, 3H), 4.03 (s, 2H), 4.2 (m, 1H), 5.17 (s,2H), 6.33 (d, J=7.5 Hz, 1H), 7.34 (m, 6H), 8.31 (t, J=5.4 Hz, 1H), 9.07(broad s, 2H), 9.90 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.4; ¹³CNMR (75 MHz, DMSO) δ 27.0, 27.2, 28.4, 43.4, 51.7, 59.3, 107.1, 118.9,127.8, 127.9, 128.1, 128.9, 137.4, 146.0, 157.5, 166.3; ES MS(M+1)342.01; HRMS Calcd. For C₁₉H₂₃N₃O₃, 341.40. Found (M+1) 342.18.

1-Benzyl-3-hydroxy-4-[(1-benzylpyrrolidin-3-ylamino)methyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 2.22 (m, 2H), 2.42 (m, 1H), 3.39 (m, 3H), 3.68(m, 1H), 4.06 (s, 2H), 4.39 (s, 2H), 5.17 (s, 2H), 6.33 (d, J=7.5 Hz,1H), 7.30-7.52 (m, 11H); ¹⁹F NMR (252 MHz, DMSO) δ 88.5; ¹³C NMR (75MHz, DMSO) δ 27.1, 43.4, 51.8, 52.1, 54.2, 54.7, 57.5, 106.9, 118.5,128.0, 128.8, 129.3, 129.8, 130.7, 131.3, 137.3, 146.2, 157.5; ESMS(M+1) 390.14; HRMS Calcd. For C₂₄H₂₇N₃O₂, 389.49. Found (M+1) 390.21.

(R)-1-Benzyl-3-hydroxy-4-[(1-phenylethylamino)methyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 1.58 (d, J=6.9 Hz, 3H), 3.74 (m, 2H), 4.44 (m,1H), 5.14 (s, 2H), 6.23 (d, J=7.2 Hz, 1H), 7.35 (m, 6H); ¹⁹F NMR (252MHz, DMSO) δ 89.4; ¹³C NMR (75 MHz, DMSO) δ 19.6, 42.6, 51.7, 58.0,106.9, 18.7, 128.0, 128.1, 128.8, 129.3, 129.4, 137.2, 137.4, 145.9,157.5; ES MS(M+1) 335.13; Anal. Calcd. For C₂₁H₂₂N₂O₂, 334.41. Found(M+1) 335.31.

1-Benzyl-3-hydroxy-4-[([1,3]dioxolan-2-ylmethylmethylamino)methyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 2.81 (s, 3H), 3.35 (d, J=3.9 Hz, 2H), 3.89 (m,2H), 4.01 (m, 2H), 4.21 (m, 2H), 5.17 (s, 2H); 5.27 (t, J=3.9 Hz, 1H),6.34 (d, J=7.2 Hz, 1H), 7.35 (m, 6H); ¹⁹F NMR (252 MHz, DMSO) δ 88.5;¹³C NMR (75 MHz, DMSO) δ; ES MS(M+1) 331.18; HRMS Calcd. For C₁₈H₂₂N₂O₄,330.38. Found (M+1) 331.16.

Category IV of the disclosed prolyl hydroxylase inhibitors relates tocompounds having the formula:

wherein A represents a ring optionally substituted by one or more R²⁰⁰units. Table IV provides non-limiting examples of this category.

TABLE IV No. A ring D1 pyrrolidin-1-yl D2 3-hydroxypyrrolidin-1-yl D32-(pyrdin-2-yl)pyrrolidin-1-yl D4 2-methylcarboxypyrrolidin-1-yl D52-(methoxymethyl)pyrrolidin-1-yl D6 thiazolidin-3-yl D7 1H-imidazol-1-ylD8 piperidin-1-yl D9 4-benzylpiperidin-1-yl D10 1,4′-bipiperidinyl-1′-ylD11 piperazin-1-yl D12 4-benzylpiperazin-1-yl D134-(2-methoxyphenyl)piperazin-1-ylmethyl D144-(6-chloropyridazin-3-yl)piperazin-1-yl D151,4-dioxa-8-azaspiro[4,5]dec-8-yl D16 morpholin-4-yl D17thiomorpholin-4-yl D18 azepan-1-yl D19 azocan-1-yl D203,4-dihydroquinolin-1(2H)-yl

The disclosed compounds of this category can be prepared by theprocedure outlined herein below in Scheme III and described in Example3.

EXAMPLE 31-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridin-2(1H)-one(8)

1-(4′-Methylbenzenesulfonyl)-3-hydroxypyridin-2(1H)-one (7): To stirredsolution of 3-[(tert-butyldimethylsilyl)oxy]pyridin-2(1H)-one (1) (4.66g, 20.7 mmol) in dry THF (150 mL), maintained at −78° C. under a drynitrogen atmosphere is added n-butyl lithium (1.6 M solution in hexane,21.0 mmol). After 20 minutes, 4-methylbenzenesulfonyl chloride (3.95 g,20.7 mmol) is added as a THF solution. The solution is allowed to warmto room temperature over one hour, the water (10 mL) is added and thecontents of the reaction vessel is extracted with EtOAc (3×), washedwith brine (1×), dried over Na₂SO₄ and concentrated. The combinedorganic layers are dried over Na₂SO₄ and concentrated. The residue istaken up in ethanol (10 mL) and treated with conc. HCl (2 mL). Themixture is allowed to stir for 1 hour and the solvent is removed underreduced pressure to afford the desired compound as a white solid. ¹H NMR(300 MHz, DMSO) δ 2.43 (s, 3H), 6.14 (t, J=6.9 Hz, 1H), 6.76 (dd, J=7.65Hz, 1.5 Hz, 1H), 7.18 (dd, J=6.6 Hz, 1.8 Hz, 1H), 7.32 (d, J=7.3 Hz,2H), 7. 98 (d, J=7.9 Hz, 2H).

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-(pyrrolidin-1-ylmethyl)pyridin-2(1H)-one(8): 1-(4′-Methylbenzenesulfonyl)-3-hydroxypyridin-2(1H)-one (7) (250mg, 0.94 mmol) and formaldehyde (200 mg, 2.07 mmol) are combined inaqueous ethanol (10 mL) and stirred for 30 minutes. Pyrrolidine (149 mg,2.07 mmol) is then added and the reaction stirred for 12 hours. Thesolvent is removed by evaporation and the residue dissolved in methanol(5 mL) and purified via prep HPLC eluting with water/acetonitrile toafford the desired product. ¹H NMR (300 MHz, DMSO) δ 1.87 (m, 2H), 1.99(m, 2H), 2.44 (s, 3H), 3.09 (m, 2H), 3.40 (m, 2H), 4.19 (s, 2H), 6.51(d, J=7.5 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.98(d, J=8.1 Hz, 1H), 9.93 (broad s, 1H); ¹⁹F NMR (252 MHz, DMSO) δ 88.4;13C NMR (75 MHz, DMSO) δ 21.5, 22.7, 50.5, 53.7, 108.7, 118.6, 119.4,128.4, 129.7, 130.1, 133.1, 146.8, 147.7, 156.2; ES MS(M+1) 349.25; HRMSCalcd. For C₁₇H₂₀N₂O₄S, 348.42. Found (M+1) 349.42.

The following are further non-limiting examples of prolyl hydroxylaseinhibitors according to this category.

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-thiazolidin-3-ylmethylpyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 2.43 (s, 3H), 2.94 (t, J=6.6 MHz, 2H), 3.18 (t,J=6.0 Hz, 2H), 3.66 (s, 2H), 4.12 (s, 2H), 6.51 (d, J=7.5 Hz, 1H), 7.51(d, J=8.4 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), ¹⁹FNMR (252 MHz, DMSO) δ 87.9; ¹³C NMR (75 MHz, DMSO) δ 21.5, 21.9, 24.6,25.8, 50.3, 51.6, 108.7, 118.6, 120.8, 129.7, 130.1, 133.1, 146.9,148.1, 156.1, 158.4, 158.8; ES MS(M+1) 367.18; HRMS Calcd. ForC₁₆H₁₈N₂O₄S₂, 366.46. Found (M+1) 367.43.

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-azocan-1ylmethylpyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 1.59 (m, 10H), 2.44 (s, 3H), 3.17 (m, 2H), 3.32(m, 2H), 4.15 (s, 2H), 6.51 (d, J=7.5 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H),7.76 (d, J=7.5 Hz, 1H), 7.98 (d, J=8.1 Hz); ¹⁹F NMR (252 MHz, DMSO) δ88.7; ¹³C NMR (75 MHz, DMSO) δ 21.5, 21.9, 23.7, 24.6, 25.8, 50.3, 51.6,108.7, 118.9, 120.8, 129.8, 130.1, 133.1, 146.9, 148.2, 156.1; ESMS(M+1) 391.18; HRMS Calcd. For C₂₀H₂₆N₂O₄S, 390.18. Found (M+1) 391.23.

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-(4-phenylpiperazin-1-ylmethyl)-pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 2.43 (s, 3H), 3.13 (m, 8H), 3.43 (s, 2H), 6.47(d, J=7.5 Hz, 1H), 6.78 (t, J=7.2 Hz, 1H), 7.21 9m, 2H), 7.50 (d, J=8.1Hz, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H); ¹³C NMR (75MHz, DMSO) δ 21.5, 42.6, 45.6, 46.2, 50.8, 51.9, 109.6, 116.4, 116.8,117.7, 120.6, 121.1, 129.5, 129.6, 129.8, 130.1, 133.2, 146.8, 149.5,156.1; ES MS(M+1) 440.15; HRMS Calcd. For C₂₃H₂₅N₃O₅S, 439.53. Found(M+1) 440.16.

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-[1,4′]Bipiperidinyl-1′-ylmethylpyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 1.43 (m, 1h), 1.67 (m, 2H), 1.82 (m, 4H), 2.19(m, 2H), 2.44 (s, 3H), 2.94 (m, 4H), 3.39 (m, 2H), 3.54 (m, 3H), 4.06(s, 2H), 6.47 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.73 (d, 7.8Hz, 1H), 7.99 (d, J=8.4 Hz, 2H); ¹⁹F NMR (252 MHz, DMSO) δ 88.7; ¹³C NMR(75 MHz, DMSO) δ 21.4, 22.9, 23.6, 48.4, 49.5, 59.4, 109.3, 114.8,117.6, 120.5, 122.7, 129.7, 130.1, 133.1, 146.9, 148.6, 156.2; ESMS(M+1) 446.19; HRMS Calcd. For C₂₃H₃₁N₃O₄S, 445.58. Found (M+1) 446.21.

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-[4-(6-chloropyridazin-3-yl)piperazin-1-ylmethyl]pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 2.44 (s, 3H), 3.17 (m, 2H), 3.46 (m, 4H), 4.17(s, 2H), 4.45 (m, 2H), 6.77 (d, J=7.8 Hz, 1H), 7.04 (m, 1H), 7.53 (m2H), 7.68 (m, 2H), 7.98 (m, 2H), 11.3 (broad s, 1H), ES MS(M+1) 476.92.HRMS Calcd. For C₂₁H₂₅ClN₅O₄S, 475.95. Found (M+1) 476.11.

Category V of HIF-1α prolyl hydroxylase inhibitors relates to compoundshaving the formula:

R represents from 1 to 5 optional substitutions for a phenyl ringhydrogen atom, R¹ and R² are each independently hydrogen or substitutedor unsubstituted C₁-C₁₀ linear or branched alkyl, wherein the alkyl unitcan be substituted by one or more units independently chosen from:

i) C₁-C₈ linear, C₃-C₈ branched, or C₃-C₈ cyclic alkoxy;

ii) hydroxy;

iii) halogen;

iv) cyano;

v) amino, C₁-C₈ mono-alkylamino, C₁-C₈ di-alkylamino;

vi) —SR⁴⁰; R⁴⁰ is hydrogen or C₁-C₄ linear or C₃-C₄ branched alkyl;

vii) substituted or unsubstituted C₆ of C₁₀ aryl;

viii) substituted or unsubstituted C₁-C₉ heterocyclic; or

ix) substituted or unsubstituted C₁-C₉ heteroaryl.

Table V provides non-limiting examples of this category of HIF-1α prolylhydroxylase inhibitors.

TABLE V No. R R¹ R² E1 4-methyl benzyl hydrogen E2 4-methyl4-methoxybenzyl hydrogen E3 4-methyl 4-fluorobenzyl hydrogen E4 4-methyl4-chlorobenzyl hydrogen E5 4-methyl 4-methylbenzyl hydrogen E6 4-methyl2-(pyridin-2-yl)ethyl hydrogen E7 4-methyl [1,3]dioxolan-2-ylmethylhydrogen E8 4-methyl tetrahydrofuran-2-ylmethyl hydrogen E9 4-methyl2-methoxyethyl hydrogen E10 4-methyl 1-hydroxy-2-methylpropan-2-ylhydrogen E11 4-methyl pyridin-4-ylmethyl hydrogen E12 4-methylfuran-2-ylmethyl hydrogen E13 4-methyl 2-(methylthio)ethyl hydrogen E144-methyl 1-phenylethyl hydrogen E15 4-methyl 3-imidazol-1-ylpropylhydrogen E16 4-methyl cycloheptyl hydrogen E17 4-methyl4-methylcyclohexyl hydrogen E18 4-methyl 1-benzylpiperidin-4-yl hydrogenE19 4-methyl azepan-2-on-3-yl hydrogen E20 4-methyl1-benzylpyrrolidin-3-yl hydrogen E21 4-methyl benzyl methyl E22 4-methyl4-methoxybenzyl methyl E23 4-methyl 4-fluorobenzyl methyl E24 4-methyl4-chlorobenzyl methyl E25 4-methyl 4-methylbenzyl methyl E26 4-methyl2-(pyridin-2-yl)ethyl methyl E27 4-methyl [1,3]dioxolan-2-ylmethylmethyl E28 4-methyl tetrahydrofuran-2-ylmethyl methyl E29 4-methyl2-methoxyethyl methyl E30 4-methyl 1-hydroxy-2-methylpropan-2-yl methylE31 4-methyl pyridin-4-ylmethyl methyl E32 4-methyl furan-2-ylmethylmethyl E33 4-methyl carboxymethyl methyl E34 4-methyl2-(methylthio)ethyl methyl E35 4-methyl 1-phenylethyl methyl E364-methyl 3-imidazol-1-ylpropyl methyl E37 4-methyl cycloheptyl methylE38 4-methyl 4-methylcyclohexyl methyl E39 4-methyl1-benzylpiperidin-4-yl methyl E40 4-methyl azepan-2-on-3-yl methyl E414-methyl 1-benzylpyrrolidin-3-yl methyl

The disclosed compounds of this category can be prepared by theprocedure outlined herein below in Scheme IV and described in Examples4.

EXAMPLE 41-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-[(benzylamino)methyl]-pyridin-2(1H)-one(9)

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-(benzylaminomethyl)pyridin-2(1H)-one(9): 1-(4′-Methylbenzenesulfonyl)-3-hydroxypyridin-2(1H)-one (7) (250mg, 0.94 mmol) and formaldehyde (200 mg, 2.07 mmol) are combined inaqueous ethanol (10 mL) and stirred for 30 minutes. Benzylamine (229 mg,2.07 mmol) is then added and the reaction stirred for 12 hours. Thesolvent is removed by evaporation and the residue dissolved in methanol(5 mL) and purified via prep HPLC eluting with water/acetonitrile toafford the desired product as the trifluoracetate salt. ¹H NMR (300 MHz,DMSO) d 2.44 (s, 3H), 3.96 (s, 2H), 4.16 (s, 2H), 6.69 (d, J=8.1 Hz),7.40 (m, 7H), 7.52 (m, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.97 (d, J=8.1 Hz,1H), 9.71 (broad s, 2H), 10.44 (broad s, 1H); ES MS(M+1) 396.67; HRMSCalcd. For C₂₀H₂₀N₂O₄S, 384.45. Found (M+1) 385.12.

The following is a further non-limiting example of this category ofHIF-1α prolyl hydroxylase inhibitors.

1-(4′-Methylbenzenesulfonyl)-3-hydroxy-4-[(2-methoxyethylamino)methyl]-pyridin-2(1H)-one:¹H NMR (300 MHz, DMSO) δ 2.43 (s, 3H), 3.12 (m, 2H), 3.29 (s, 3H), 3.56(t, J=5.1 Hz, 2H), 3.99 (s, 2H), 6.51 (d, J=7.5 Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.98 (d, J=8.1 Hz); ¹⁹F NMR (252 MHz,DMSO) δ 88.6; ¹³C NMR (75 MHz, DMSO) δ 21.5, 43.8, 46.2, 46.5, 58.5,67.2, 106.7, 119.2, 120.2, 123.9, 128.4, 129.7, 130.1, 133.1, 146.8,147.0, 156.0; ES MS(M+1) 353.12. HRMS Calcd. For C₁₆H₂₀N₂O₅S, 352.41.Found (M+1) 353.11.

Category VI of HIF-1α prolyl hydroxylase inhibitors relates to compoundshaving the formula:

wherein L is chosen from CH₂ or SO₂, and Z is substituted orunsubstituted phenyl. Non-limiting examples of inhibitors according tothis category are disclosed in Table VI below.

TABLE VI No. L Z F1 CH₂ 2-chlorophenyl F2 CH₂ 3-chlorophenyl F3 CH₂4-chlorophenyl F4 CH₂ 2-fluorophenyl F5 CH₂ 3-fluorophenyl F6 CH₂4-fluorophenyl F7 CH₂ 2,3-dichlorophenyl F8 CH₂ 2,4-dichlorophenyl F9CH₂ 2,5-dichlorophenyl F10 CH₂ 2,6-dichlorophenyl F11 CH₂3,4-dichlorophenyl F12 CH₂ 3,5-dichlorophenyl F13 CH₂ 2,3-difluorophenylF14 CH₂ 2,4-difluorophenyl F15 CH₂ 2,5-difluorophenyl F16 CH₂2,6-difluorophenyl F17 CH₂ 3,4-difluorophenyl F18 CH₂ 3,5-difluorophenylF19 CH₂ 2-cyanophenyl F20 CH₂ 3-cyanophenyl F21 CH₂ 4-cyanophenyl F22SO₂ 2-chlorophenyl F23 SO₂ 3-chlorophenyl F24 SO₂ 4-chlorophenyl F25 SO₂2-fluorophenyl F26 SO₂ 3-fluorophenyl F27 SO₂ 4-fluorophenyl F28 SO₂2,3-dichlorophenyl F29 SO₂ 2,4-dichlorophenyl F30 SO₂ 2,5-dichlorophenylF31 SO₂ 2,6-dichlorophenyl F32 SO₂ 3,4-dichlorophenyl F33 SO₂3,5-dichlorophenyl F34 SO₂ 2,3-difluorophenyl F35 SO₂ 2,4-difluorophenylF36 SO₂ 2,5-difluorophenyl F37 SO₂ 2,6-difluorophenyl F38 SO₂3,4-difluorophenyl F39 SO₂ 3,5-difluorophenyl F40 SO₂ 2-cyanophenyl F41SO₂ 3-cyanophenyl F42 SO₂ 4-cyanophenyl

The compounds encompassed within this category can be prepared accordingto Scheme I for Z equal to CH₂ and according to Scheme III for Z equalto SO₂.

Pharmaceutically Acceptable Salts

The disclosed compounds useful for treating colitis and otherinflammatory bowel diseases and syndromes can be in the form of apharmaceutically acceptable salt. Pharmaceutically acceptable salts canbe used by the formulator to provide a form of the disclosed inhibitorthat is more compatible with the intended delivery of the inhibitor to asubject or for compatibility of formulation.

The following are examples of procedures for preparing thepharmaceutically acceptable salt of the disclosed inhibitor,tert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate.

A suspension oftert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate(242 mg, 0.56 mmol) in MeOH (15 mL) was heated at reflux until ahomogeneous solution was obtained. Heating was stopped and 0.1N HCl (6.7mL, 1.2 eq.) was added while still hot and the solution was cooled toroom temperature. The volatiles were evaporated under reduced pressureand the amorphous residue was crystallized in acetone (5 mL). The solidwas collected by filtration.

A suspension oftert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate(217 mg, 0.5 mmol) in MeOH (15 mL) was heated at reflux until ahomogeneous solution was obtained. Heating was stopped andmethanesulfonic acid (115.2 mg, 1.2 eq.) was added while still hot andthe solution was cooled to room temperature. The volatiles wereevaporated under reduced pressure and the amorphous residue wascrystallized in acetone (5 mL). The solid was collected by filtration.

Table VII herein below provides examples of pharmaceutically acceptablesalts oftert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylateformed from organic and inorganic acids. Start

TABLE VII Acid Yield Purity* M.P. (° C.) color Free base — 99.3% 183-184pink HCl 90% 99.7% 185-186 white H₂SO₄ 93% 99.7% 175 (dec.) slightlypink p-toluenesulfonyl 74% 99.8% 185-186 white methanesulfonyl 79% 99.9%155-157 white *Determined by HPLC analysis

¹H NMR analysis was used to determine the form of the salt, for example,that the mesylate salt formed herein above had the following formula:

¹H NMR analysis was used to determine at which position in the moleculethat salt formation was taking place. The chemical shifts for theprotons on the methylene group bridging the piperazine and thepyridinone rings shifted from 3.59 ppm in the free base to 4.31 ppm ofthe salt. In addition, the piperazine methylene groups adjacent to thetertiary amine shifted from 2.50 ppm to approximately 3.60 ppm. Thechemical shifts for the remaining protons were largely unchanged. Thesedata indicate that the tertiary amine nitrogen of the piperazine ring isprotonated in salt forms. In addition, integration of the methyl protonsof the methane sulfonyl unit relative to the core compound indicates thepresence of one equivalent of the acid.

The formulator can determine the solubility of the pharmaceuticallyacceptable salts of the disclosed inhibitors by any method desirable.The following is a non-limiting example of a procedure for evaluatingthe solubility of a salt of a disclosed inhibitor. A suspension oftert-butyl-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylatemethanesulfonate (26.6 mg) in distilled deionized water (3.0 mL) issonicated for 20 min with water bath temperature under 25° C. Thesuspension is filtered to remove any insoluble salt. The clear filtratesolution (200 μL) is diluted with distilled deionized water (800 μL) andsubjected to HPLC analysis. The following are results for thepharmaceutically acceptable salts outlined in Table VII above.

Solubility Salt (mg/mL) Purity* Free base ~0.001 99.3% hydrochloride 5.999.7% hydrogensulfonate 13.2 99.7% p-toluenesulfonate 2.3 99.8%methanesulfonate 16.6   99% *Determined by HPLC analysis

The following are non-limiting examples of other acids that can be usedto form pharmaceutically acceptable salts of the disclosed inhibitors:acetate, citrate, maleate, succinate, lactate, glycolate, tartrate,bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate,formate, propionate, butyrate, pyruvate, oxalate, malonate, fumarate,and the like.

Acute and chronic inflammation of the bowel is caused by a number ofdiseases. Typically the epithelial cells on the surface of mucosaltissue have an induced state of hypoxia due to the presence ofinflammation. The body's response to this hypoxic condition is toincrease the presence of hypoxia inducible factor-1 alpha (HIF-1α) whichdrives the expression of downstream HIF-1 target genes, inter alia,erythropoietin. As such, HIF-1α is an important mediator in the body'sresponse to inflammation. The cellular concentration of HIF-1α isregulated by prolyl hydroxylase enzymes that serve to destabilize HIF-1αduring periods of normoxia resulting in the destruction of this protein.

Inhibition of HIF-1α prolyl hydroxylase thus leads to increasedstabilization of HIF-1α resulting in up regulation of HIF-1 which leadsto a corresponding increased response to inflammation. In subjectssuffering from one or more inflammatory epithelial diseases, treatmentwith one or more effective HIF-1α prolyl hydroxylase inhibitors canincrease the level of the body's cellular inflammatory response. Inaddition, during periods of low inflammation in the case of chronicdiseases, HIF-1α prolyl hydroxylase inhibitors can increase the amountof epithelial cell healing over that which the body would normallyprovide. As such, administration of one or more HIF-1α prolylhydroxylase inhibitors to a subject suffering from an inflammatorydisease such as Crohn's disease, or alternatively to a subject diagnosedwith an inflammatory disease provides a method for curing, controlling,mediating, reducing, or otherwise affecting the severity of thecondition.

Methods

Disclosed herein are methods for treating a subject having or sufferingfrom one or more diseases or conditions affecting intestinal epithelialtissue. In one aspect, disclosed herein is a method for treating asubject having an inflammatory bowel disease, comprising administeringto the subject an effective amount of one or more of the disclosedHIF-1α prolyl hydroxylase inhibitors or pharmaceutically acceptablesalts thereof. Non-limiting examples of inflammatory bowel diseasesincludes Crohn's disease, ulcerative colitis, collagenous colitis,lymphocytic colitis, ischemic colitis, diversion colitis, Behcet'ssyndrome, and indeterminate colitis. As such, disclosed are thefollowing methods. The disclosed methods also relate to methods fortreating a subject that is diagnosed with one or more of the followingconditions, syndromes, illnesses, pathologies, maladies, diseases, andthe like.

A method for treating Crohn's disease in a subject, comprisingadministering to the subject an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof. One embodiment of this method relates toadministering to a subject with Crohn's disease an effective amount of apharmaceutical composition as disclosed herein. Another embodiment ofthis method relates to administering to a subject with Crohn's diseasean effective amount of a pharmaceutical composition as disclosed hereinthat comprises an effective amount of one or more of the disclosedHIF-1α prolyl hydroxylase inhibitors or pharmaceutically acceptablesalts thereof in combination with an effective amount of one or moreother pharmaceutical agents.

A method for treating ulcerative colitis in a subject, comprisingadministering to the subject an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof. One embodiment of this method relates toadministering to a subject with ulcerative colitis an effective amountof a pharmaceutical composition as disclosed herein. Another embodimentof this method relates to administering to a subject with ulcerativecolitis an effective amount of a pharmaceutical composition as disclosedherein that comprises an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof in combination with an effective amount of oneor more other pharmaceutical agents.

A method for treating collagenous colitis in a subject, comprisingadministering to the subject an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof. One embodiment of this method relates toadministering to a subject with collagenous colitis an effective amountof a pharmaceutical composition as disclosed herein. Another embodimentof this method relates to administering to a subject with collagenouscolitis an effective amount of a pharmaceutical composition as disclosedherein that comprises an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof in combination with an effective amount of oneor more other pharmaceutical agents.

A method for treating lymphocytic colitis in a subject, comprisingadministering to the subject an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof. One embodiment of this method relates toadministering to a subject with lymphocytic colitis an effective amountof a pharmaceutical composition as disclosed herein. Another embodimentof this method relates to administering to a subject with lymphocyticcolitis an effective amount of a pharmaceutical composition as disclosedherein that comprises an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof in combination with an effective amount of oneor more other pharmaceutical agents.

A method for treating ischemic colitis in a subject, comprisingadministering to the subject an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof. One embodiment of this method relates toadministering to a subject with ischemic colitis an effective amount ofa pharmaceutical composition as disclosed herein. Another embodiment ofthis method relates to administering to a subject with ischemic colitisan effective amount of a pharmaceutical composition as disclosed hereinthat comprises an effective amount of one or more of the disclosedHIF-1α prolyl hydroxylase inhibitors or pharmaceutically acceptablesalts thereof in combination with an effective amount of one or moreother pharmaceutical agents.

A method for treating diversion colitis in a subject, comprisingadministering to the subject an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof. One embodiment of this method relates toadministering to a subject with diversion colitis an effective amount ofa pharmaceutical composition as disclosed herein. Another embodiment ofthis method relates to administering to a subject with diversion colitisan effective amount of a pharmaceutical composition as disclosed hereinthat comprises an effective amount of one or more of the disclosedHIF-1α prolyl hydroxylase inhibitors or pharmaceutically acceptablesalts thereof in combination with an effective amount of one or moreother pharmaceutical agents.

A method for treating ulcerative colitis in a subject, comprisingadministering to the subject an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof. One embodiment of this method relates toadministering to a subject with ulcerative colitis an effective amountof a pharmaceutical composition as disclosed herein. Another embodimentof this method relates to administering to a subject with ulcerativecolitis an effective amount of a pharmaceutical composition as disclosedherein that comprises an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof in combination with an effective amount of oneor more other pharmaceutical agents.

A method for treating Behcet's syndrome in a subject, comprisingadministering to the subject an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof. One embodiment of this method relates toadministering to a subject with Behcet's syndrome an effective amount ofa pharmaceutical composition as disclosed herein. Another embodiment ofthis method relates to administering to a subject with Behcet's syndromean effective amount of a pharmaceutical composition as disclosed hereinthat comprises an effective amount of one or more of the disclosedHIF-1α prolyl hydroxylase inhibitors or pharmaceutically acceptablesalts thereof in combination with an effective amount of one or moreother pharmaceutical agents.

Further disclosed herein are methods for treating a subject having orsuffering from one or more inflammatory epithelial diseases conditions,syndromes, illnesses, pathologies, maladies and the like. In one aspect,disclosed herein is a method for treating a subject having inflammatoryepithelial disease of the respiratory tract, comprising administering tothe subject an effective amount of one or more of the disclosed HIF-1αprolyl hydroxylase inhibitors or pharmaceutically acceptable saltsthereof. One embodiment of this method relates to administering to asubject having inflammatory epithelial disease of the respiratory tractan effective amount of a pharmaceutical composition as disclosed herein.Another embodiment of this method relates to administering to a subjecthaving inflammatory epithelial disease of the respiratory tract aneffective amount of a pharmaceutical composition as disclosed hereinthat comprises an effective amount of one or more of the disclosedHIF-1α prolyl hydroxylase inhibitors or pharmaceutically acceptablesalts thereof in combination with an effective amount of one or moreother pharmaceutical agents.

In another aspect, disclosed herein is a method for treating a subjecthaving inflammatory epithelial disease of the mucosa, comprisingadministering to the subject an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof. One embodiment of this method relates toadministering to a subject having inflammatory epithelial disease of themucosa an effective amount of a pharmaceutical composition as disclosedherein. Another embodiment of this method relates to administering to asubject having inflammatory epithelial disease of the mucosa aneffective amount of a pharmaceutical composition as disclosed hereinthat comprises an effective amount of one or more of the disclosedHIF-1α prolyl hydroxylase inhibitors or pharmaceutically acceptablesalts thereof in combination with an effective amount of one or moreother pharmaceutical agents.

In a further aspect, disclosed herein is a method for treating a subjecthaving inflammatory epithelial disease of the skin, comprisingadministering to the subject an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof. One embodiment of this method relates toadministering to a subject having inflammatory epithelial disease of theskin an effective amount of a pharmaceutical composition as disclosedherein. Another embodiment of this method relates to administering to asubject having inflammatory epithelial disease of the skin an effectiveamount of a pharmaceutical composition as disclosed herein thatcomprises an effective amount of one or more of the disclosed HIF-1αprolyl hydroxylase inhibitors or pharmaceutically acceptable saltsthereof in combination with an effective amount of one or more otherpharmaceutical agents.

In a still further aspect, disclosed herein is a method for treating asubject having inflammatory epithelial disease of the GI tract,comprising administering to the subject an effective amount of one ormore of the disclosed HIF-1α prolyl hydroxylase inhibitors orpharmaceutically acceptable salts thereof. One embodiment of this methodrelates to administering to a subject having inflammatory epithelialdisease of the GI tract an effective amount of a pharmaceuticalcomposition as disclosed herein. Another embodiment of this methodrelates to administering to a subject having inflammatory epithelialdisease of the GI tract an effective amount of a pharmaceuticalcomposition as disclosed herein that comprises an effective amount ofone or more of the disclosed HIF-1α prolyl hydroxylase inhibitors orpharmaceutically acceptable salts thereof in combination with aneffective amount of one or more other pharmaceutical agents.

In a yet still further aspect, disclosed herein is a method for treatinga subject having inflammatory epithelial disease of the lining of one ormore major organs and/or endocrine glands, comprising administering tothe subject an effective amount of one or more of the disclosed HIF-1αprolyl hydroxylase inhibitors or pharmaceutically acceptable saltsthereof. One embodiment of this method relates to administering to asubject having inflammatory epithelial disease of the lining of one ormore major organs and/or endocrine glands an effective amount of apharmaceutical composition as disclosed herein. Another embodiment ofthis method relates to administering to a subject having inflammatoryepithelial disease of the lining of one or more major organs and/orendocrine glands an effective amount of a pharmaceutical composition asdisclosed herein that comprises an effective amount of one or more ofthe disclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof in combination with an effective amount of oneor more other pharmaceutical agents.

In a still another aspect, disclosed herein is a method for treating asubject having inflammatory epithelial disease of the vascular tissue,comprising administering to the subject an effective amount of one ormore of the disclosed HIF-1α prolyl hydroxylase inhibitors orpharmaceutically acceptable salts thereof. One embodiment of this methodrelates to administering to a subject having inflammatory epithelialdisease of the vascular tissue an effective amount of a pharmaceuticalcomposition as disclosed herein. Another embodiment of this methodrelates to administering to a subject having inflammatory epithelialdisease of the vascular tissue an effective amount of a pharmaceuticalcomposition as disclosed herein that comprises an effective amount ofone or more of the disclosed HIF-1α prolyl hydroxylase inhibitors orpharmaceutically acceptable salts thereof in combination with aneffective amount of one or more other pharmaceutical agents.

Still further disclosed herein is the use of an effective amount of oneor more of the disclosed HIF-1α prolyl hydroxylase inhibitors orpharmaceutically acceptable salts thereof for making a medicament totreat an inflammatory disease in intestinal epithelial tissue, such asinflammatory bowel disease, including Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischemic colitis,diversion colitis, Behcet's syndrome, and indeterminate colitis. Alsodisclosed herein is the use of an effective amount of one or more of thedisclosed HIF-1α prolyl hydroxylase inhibitors or pharmaceuticallyacceptable salts thereof for making a medicament to treat aninflammatory epithelial disease, including the respiratory tract,mucosa, skin, GI tract, lining of major organs and endocrine glands, andvascular tissue.

Formulations Medicaments and Pharmaceutical Compositions

The present disclosure further relates to pharmaceutical compositionsthat can be used as a method for treating one or more of the discloseddiseases. In addition, the disclosed formulations can be used for makinga medicament or a pharmaceutical composition useful for treating one ormore of the disclosed diseases, conditions, ailments, syndromes, and thelike. The disclosed medicaments or pharmaceutical compositions comprisean effective amount of one or more HIF-1α prolyl hydroxylase inhibitorsor pharmaceutically acceptable salts thereof according to the presentdisclosure.

One aspect of the disclosed compositions comprises:

-   -   a) an effective amount of one or more of the disclosed HIF-1α        prolyl hydroxylase inhibitors or a pharmaceutically acceptable        salt thereof; and    -   b) one or more excipients.

For the purposes of the present disclosure the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent disclosure and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present disclosure have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

Non-limiting examples of compositions according to the presentdisclosure include:

-   -   a) from about 0.001 mg to about 1000 mg of one or more disclosed        HIF-1α prolyl hydroxylase inhibitors or a pharmaceutically        acceptable salt thereof; and    -   b) one or more excipients.

Another example according to the present disclosure relates to thefollowing compositions:

-   -   a) from about 0.01 mg to about 100 mg of one or more disclosed        HIF-1α prolyl hydroxylase inhibitors or a pharmaceutically        acceptable salt thereof; and    -   b) one or more excipients.

A further example according to the present disclosure relates to thefollowing compositions:

-   -   a) from about 0.1 mg to about 10 mg of one or more disclosed        HIF-1α prolyl hydroxylase inhibitors or a pharmaceutically        acceptable salt thereof; and    -   b) one or more excipients.

A still further example of compositions according to the presentdisclosure comprise:

-   -   a) an effective amount of one or more disclosed HIF-1α prolyl        hydroxylase inhibitors or a pharmaceutically acceptable salt        thereof; and    -   b) one or more chemotherapeutic agents or chemotherapeutic        compounds as further described herein.

One category of chemotherapeutic agents or chemotherapeutic compoundsincludes cytotoxic drugs, for example, 6-hydroxymethylacylfulvene,cyclophosphamide, dacarbazine, carmustine, doxorubicin, andmethotrexate.

Another category of chemotherapeutic agents or chemotherapeuticcompounds include, but are not limited to: acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine;dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel;doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifenecitrate; dromostanolone propionate; duazomycin; edatrexate; eflornithinehydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;estramustine; estramustine phosphate sodium; etanidazole; etoposide;etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine;fenretinide; floxuridine; fludarabine phosphate; fluorouracil;flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabinehydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide;ilmofosine; interleukin II (including recombinant interleukin II, orrIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1;interferon alfa-n3; interferon beta-I a; interferon gamma-I b;iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole;leuprolide acetate; liarozole hydrochloride; lometrexol sodium;lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; zorubicin hydrochloride. Other anti-cancer drugs include,but are not limited to: 20-epi-1,25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;eflornithine; elemene; emitefur; epirubicin; epristeride; estramustineanalogue; estrogen agonists; estrogen antagonists; etanidazole;etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide;filgrastim; finasteride; flavopiridol; flezelastine; fluasterone;fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane;fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathioneinhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;insulin-like growth factor-1 receptor inhibitor; interferon agonists;interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-;iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. In one embodiment, the anti-cancer drug is 5-fluorouracil,taxol, or leucovorin.

Other chemotherapeutic agents that can be used in combination with thedisclosed HIF-1α inhibitors include, but are not limited to, mitoticinhibitors (vinca alkaloids). These include vincristine, vinblastine,vindesine and Navelbine™ (vinorelbine, 5′-noranhydroblastine). In yetother embodiments, chemotherapeutic cancer agents include topoisomeraseI inhibitors, such as camptothecin compounds. As used herein,“camptothecin compounds” include Camptosar™ (irinotecan HCL), Hycamtin™(topotecan HCL) and other compounds derived from camptothecin and itsanalogues. Another category of chemotherapeutic cancer agents that maybe used in the methods and compositions disclosed herein arepodophyllotoxin derivatives, such as etoposide, teniposide andmitopodozide. The present disclosure further encompasses otherchemotherapeutic cancer agents known as alkylating agents, whichalkylate the genetic material in tumor cells. These include withoutlimitation cisplatin, cyclophosphamide, nitrogen mustard, trimethylenethiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracilmustard, chlomaphazin, and dacarbazine. The disclosure encompassesantimetabolites as chemotherapeutic agents. Examples of these types ofagents include cytosine arabinoside, fluorouracil, methotrexate,mercaptopurine, azathioprime, and procarbazine. An additional categoryof chemotherapeutic cancer agents that may be used in the methods andcompositions disclosed herein include antibiotics. Examples includewithout limitation doxorubicin, bleomycin, dactinomycin, daunorubicin,mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerousliposomal formulations commercially available for these compounds. Thepresent disclosure further encompasses other chemotherapeutic canceragents including without limitation anti-tumor antibodies, dacarbazine,azacytidine, amsacrine, melphalan, ifosfamide and mitoxantrone.

The disclosed HIF-1α prolyl hydroxylase inhibitors herein can beadministered in combination with other anti-tumor agents, includingcytotoxic/antineoplastic agents and anti-angiogenic agents.Cytotoxic/anti-neoplastic agents are defined as agents which attack andkill cancer cells. Some cytotoxic/anti-neoplastic agents are alkylatingagents, which alkylate the genetic material in tumor cells, e.g.,cis-platin, cyclophosphamide, nitrogen mustard, trimethylenethiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracilmustard, chlomaphazin, and dacabazine. Other cytotoxic/anti-neoplasticagents are antimetabolites for tumor cells, e.g., cytosine arabinoside,fluorouracil, methotrexate, mercaptopuirine, azathioprime, andprocarbazine. Other cytotoxic/anti-neoplastic agents are antibiotics,e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin,mitomycin, mytomycin C, and daunomycin. There are numerous liposomalformulations commercially available for these compounds. Still othercytotoxic/anti-neoplastic agents are mitotic inhibitors (vincaalkaloids). These include vincristine, vinblastine and etoposide.Miscellaneous cytotoxic/anti-neoplastic agents include taxol and itsderivatives, L-asparaginase, anti-tumor antibodies, dacarbazine,azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, andvindesine.

A yet still further example of compositions according to the presentdisclosure comprise:

-   -   a) an effective amount of one or more disclosed HIF-1α prolyl        hydroxylase inhibitors or a pharmaceutically acceptable salt        thereof; and    -   b) one or more vaccines for treatment of an infectious disease.

The disclosed compositions and the form of pharmaceutical preparationscomprising the compounds useful for treating colitis and otherinflammatory bowel diseases and syndromes alone, or in combination withanother drug or other therapeutic agent, inter alia, chemotherapeuticagent or chemotherapeutic compound, can vary according to the intendedroute of administration.

Orally administered preparations can be in the form of solids, liquids,emulsions, suspensions, or gels, or in dosage unit form, for example astablets or capsules. Tablets can be compounded in combination with otheringredients customarily used, such as tale, vegetable oils, polyols,gums, gelatin, starch, and other carriers. The compounds useful fortreating colitis and other inflammatory bowel diseases and syndromes canbe dispersed in or combined with a suitable liquid carrier in solutions,suspensions, or emulsions.

Parenteral compositions intended for injection, either subcutaneously,intramuscularly, or intravenously, can be prepared as liquids or solidforms for solution in liquid prior to injection, or as emulsions. Suchpreparations are sterile, and liquids to be injected intravenouslyshould be isotonic. Suitable excipients are, for example, water,dextrose, saline, and glycerol.

Administration of pharmaceutically acceptable salts of the substancesdescribed herein is included within the scope of the present disclosure.Such salts can be prepared from pharmaceutically acceptable non-toxicbases including organic bases and inorganic bases. Salts derived frominorganic bases include sodium, potassium, lithium, ammonium, calcium,magnesium, and the like. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, basic amino acids, and the like. For a helpfuldiscussion of pharmaceutical salts, see S. M. Berge et al., Journal ofPharmaceutical Sciences 66:1-19 (1977) the disclosure of which is herebyincorporated by reference.

Substances for injection can be prepared in unit dosage form in ampules,or in multidose containers. The compounds useful for treating colitisand other inflammatory bowel diseases and syndromes or compositionscomprising one or more compounds useful for treating colitis and otherinflammatory bowel diseases and syndromes to be delivered can be presentin such forms as suspensions, solutions, or emulsions in oily orpreferably aqueous vehicles. Alternatively, the salt of the HIF-1αprolyl hydroxylase inhibitor can be in lyophilized form forreconstitution, at the time of delivery, with a suitable vehicle, suchas sterile pyrogen-free water. Both liquids as well as lyophilized formsthat are to be reconstituted will comprise agents, preferably buffers,in amounts necessary to suitably adjust the pH of the injected solution.For any parenteral use, particularly if the formulation is to beadministered intravenously, the total concentration of solutes should becontrolled to make the preparation isotonic, hypotonic, or weaklyhypertonic. Nonionic materials, such as sugars, are preferred foradjusting tonicity, and sucrose is particularly preferred. Any of theseforms can further comprise suitable formulatory agents, such as starchor sugar, glycerol or saline. The compositions per unit dosage, whetherliquid or solid, can contain from 0.1% to 99% of polynucleotidematerial.

Procedures EGLN-1 Activity Assay

The EGLN-1 (or EGLN-3) enzyme activity is determined using massspectrometry (matrix-assisted laser desorption ionization,time-of-flight MS, MALDI-TOF MS. Recombinant human EGLN-1-179/426 isprepared as described above and in the Supplemental Data. Full-lengthrecombinant human EGLN-3 is prepared in a similar way, however it isnecessary to use the His-MBP-TVMV-EGLN-3 fusion for the assay due to theinstability of the cleaved protein. For both enzymes, the HIF-1α peptidecorresponding to residues 556-574 is used as substrate. The reaction isconducted in a total volume of 50 μL containing TrisCl (5 mM, pH 7.5),ascorbate (120 μM), 2-oxoglutarate (3.2 μM), HIF-1α (8.6 μM), and bovineserum albumin (0.01%). The enzyme, quantity predetermined to hydroxylate20% of substrate in 20 minutes, is added to start the reaction. Whereinhibitors are used, compounds are prepared in dimethyl sulfoxide at10-fold final assay concentration. After 20 minutes at room temperature,the reaction is stopped by transferring 10 μL of reaction mixture to 50μL of a mass spectrometry matrix solution (α-cyano-4-hydroxycinnamicacid, 5 mg/mL in 50% acetonitrile/0.1% TFA, 5 mM NH₄PO₄). Twomicroliters of the mixture is spotted onto a MALDI-TOF MS target platefor analysis with an Applied Biosystems (Foster City, Calif.) 4700Proteomics Analyzer MALDI-TOF MS equipped with a Nd:YAG laser (355 nm, 3ns pulse width, 200 Hz repetition rate). Hydroxylated peptide product isidentified from substrate by the gain of 16 Da. Data defined as percentconversion of substrate to product is analyzed in GraphPad Prism 4 tocalculate IC₅₀ values.

VEGF ELISA Assay

HEK293 cells are seeded in 96-well poly-lysine coated plates at 20,000cells per well in DMEM (10% FBS, 1% NEAA, 0.1% glutamine). Followingovernight incubation, the cells are washed with 100 μL of Opti-MEM(Gibco, Carlsbad, Calif.) to remove serum. Compound in DMSO is seriallydiluted (beginning with 100 μM) in Opti-MEM and added to the cells. Theconditioned media is analyzed for VEGF with a Quantikine human VEGFimmunoassay kit (R&D Systems, Minneapolis, Minn.). Optical densitymeasurements at 450 nm are recorded using the Spectra Max 250 (MolecularDevices, Sunnyvale, Calif.). Data defined as % of DFO stimulation isused to calculate EC₅₀ values with GraphPad Prism 4 software (San Diego,Calif.).

Mouse Ischemic Hindlimb Study

All animal work is conducted in accordance with the Guide for the Careand Use of Laboratory Animals (National Academy of Sciences; Copyright©1996). Used in these experiments were 9-10 week old male C57Bl/6 micefrom Charles River Laboratory (Portage, Mich.). The mice are orallydosed with vehicle (aqueous carbonate buffer, 50 mM; pH 9.0) or with thecompound to be tested in vehicle at 50 mg/kg or 100 mg/kg. The animalsare dosed three times: day 1 at 8 AM and 5 PM, and on day 2 at 8 AM. Onehour after the first dose, unilateral arterial ligation is performedunder anesthesia using isoflurane. The femoral artery is ligatedproximal to the origin of the popliteal artery. The contralateral limbundergoes a sham surgical procedure. Ligation is performed in analternating fashion between right and left hindlimbs. Two hours afterthe 8 AM dosing on day 2, blood is obtained by ventricular stick whilethe mice are anesthetized with isoflurane. Serum samples for EPOanalysis are obtained using gel clot serum separation tubes. Heart,liver, and gastrocnemius muscles are harvested, snap-frozen in liquidnitrogen, and stored in −80° C. until use.

Mouse Serum EPO Assay

The mouse serum EPO is detected using Mouse Quantikine ErythropoietinELISA kit from R&D Systems according to manufacturer's instructions.

Mouse Tissue HIF Western Blot Analysis

Tissues from mice stored at −80° C. are powdered with mortar and pestlechilled with liquid nitrogen. Nuclear extracts are prepared using anNE-PER kit (Pierce Biotechnology). For immunoprecipitation, nuclearextract is added to monoclonal antibody to HIF-1α (Novus, Littleton,Colo.) at a tissue to antibody ratio of 200:1. The suspension isincubated in a conical micro centrifuge tube for 4 hours at 4° C.Protein A/G-coupled agarose beads (40 μL of a 50% suspension) are thenadded to the tube. Following overnight tumbling at 4° C., the beads arewashed 3 times with ice-cold phosphate buffered saline. The beads arethen prepared for SDS-PAGE with 40 μL of Laemmli sample buffer. Proteinsseparated on SDS-PAGE are transferred onto nitrocellulose sheets withXCell-II Blot Module system (Invitrogen, Carlsbad, Calif.). The blotsare blocked with 5% BSA prior to incubation with a rabbit antibody toHIF-1α at 1:100 dilution (Novus). The blots are then washed withTris-buffered saline/Tween-20 buffer and incubated with horseradishperoxidase-conjugated goat anti-rabbit secondary antibody (Pierce,Rockford, Ill.). Blots are developed with the ECL reagent (Amersham,Piscataway, N.J.). Images of blots are captured with an Epson Expression1600 scanner.

Table VIII below provides non-limiting examples of the in vivo responsefor compounds according to the present disclosure, for example, HIFPH2(EGLN1) inhibition and VEGF stimulation.

TABLE VIII HIFPH2 VEGF No. Compound IC₅₀ (μM) IC₅₀ (μM) C17

11 27.4 C35

12 42.5 C14

12 20.6 B5

9 53 C33

16 53 B14

11 78 C19

12 62.9 B9

17 12.6 A18

18 29.2 D10

4.4 27 D14

12 19 C1

12 42 A41

14 16.6 E33

21 2.1 F3

1.2 7.4 F2

5 >100

Compound F2 was further tested in the mouse serum EPO assay describedherein above and found to have an EPO EC₅₀=14 μM.

The disclosed compounds, compositions and methods stabilize HIF-1α andHIF-2α, as well as other factors that are present in a compromisedimmune system or which is depleted or over taxed by the presence of adisease state and the manifestations of the disease state, inter alia,diarrhea and intestinal pain. The disclosed compounds can be used totreat colitis and other inflammatory bowel diseases, inter alia,indeterminate colitis, Crohn's disease, irritable bowel syndrome andischemic colitis and can be co-administered with other bowel diseasetherapy drug.

Induced Colitis Study

Colitis was induced in the subject animals using2,4,6-trinitrobenzenesulfonic acid (TNBS) as described in Karhausen J O,et al. “Epithelial hypoxia inducible factor-1 is protective in murineexperimental colitis.” J. Clin. Invest. 2004; 114:1098-1106. Briefly,mice were sensitized by epicutaneous application of 1% TNBS(Sigma-Aldrich) in 100% ethanol on days 1-7, followed by intrarectaladministration of 5 μL/g body weight of 2.5% TNBS solution in 50%ethanol on day +7. Vehicle-control animals received a correspondingvolume of 50% ethanol alone. Only animals that showed an initialresponse to treatment were included in the study; this response wasdefined as a 5% loss of weight after induction of colitis. As a furtherparameter, colon length was determined by measurement of the distancefrom the most distal aspect of the cecum to the most terminal aspect ofthe rectum.

Compound A41 was administered daily via 100 mL subcutaneous injection tothe scruff of the neck. Animals were treated with either 0.3, 1.0, or5.0 mg/kg of a compound disclosed in Table VIII or 100 μL cyclodextrinvehicle. Molting and baldness was observed at the injection sites in allgroups. Mild fibrosis was also observed during post-mortem examinationdue to repeated injection at the site of the scruff and vehicle buildup.

Animals' weights were measured every 24 hours over the course of theexperiment from one day prior to disease induction (Day −1). Uponsacrifice, colon length was measure to assess fibrosis and shortening.The colons were excised for analysis. Samples were taken and fixed in 4%formalin for histological analysis. Blood was taken by cardiac puncturefor hematocrit analysis and the remainder stored for serum analysis.

FIG. 1 depicts the results of this study. The control group that did notreceive TNSB-induced colitis and only received vehicle is shown by theline indicated with solid circles (). This line is flat and shows thatessentially no weight was lost by this group. The data represented bysolid squares (▪) represent control animals that had TNSB-inducedcolitis and only received pre-treatment with vehicle. Therefore, for thetwo groups of animals not receiving a pre-treatment dose of a compounddisclosed in Table VIII, solid circles () represent healthy animalswhile solid squares (▪) represent animals with TNSB-induced colitis.Comparing these two lines, it is evidenced that TNSB-induced colitiscaused at least about 20% weight loss in untreated animals havinginduced disease.

Animals having TNSB-induced colitis that were pre-treated with 5 mg/kgof a compound disclosed in Table VIII (open circles (◯)) maintainedtheir weight during the course of this study. Animals withoutTNSB-induced colitis that were pre-treated with 5 mg/kg of a compounddisclosed in Table VIII (solid triangles (▴)) had a slight weight lossbut the body mass returned to near normal during the course of thisstudy.

Animals having TNSB-induced colitis that were pre-treated with 1 mg/kgof a compound disclosed in Table VIII (solid diamonds (♦)) lost about10% of their body mass by day 1, but began to recover body mass duringthe balance of the study. Animals having TNSB-induced colitis that werepre-treated with 0.3 mg/kg of a compound disclosed in Table VIII (solidinverted triangles (▾)) lost less of their body mass at a slower rate byday 3.

FIGS. 2 a, 2 b, and 2 c depict the reversal of three clinical diseaseindicators for animals within 4 days of the study. Colon length is amarker of colonic inflammation and is reflected as increased shorteningdue to increased fibrosis associated with the inflammation.

FIG. 2 a depicts the percent colon length found in the followingtreatment groups: (A) healthy mice; (B) mice having TNBS-induced colitistreated with 5 mg/kg a compound disclosed in Table VIII from Day −1; (C)mice having TNBS-induced colitis treated with 5 mg/kg a compounddisclosed in Table VIII from Day +2; and (D) mice having TNBS-inducedcolitis receiving only vehicle.

FIG. 2 b depicts the disease activity scores for the animals treated inthis study. Severity of inflammation was documented macroscopically,considering changes of bodyweight and general appearance (hair,liveliness). Stools and rectal bleeding, and color, distension andserosal appearance of the colon directly after opening of the abdomenwere scored. A maximum macroscopic score of 12 points was allocated,according to the following: as adolescent mice gain at least 5%bodyweight per week, change of bodyweight of more than 5% was scored 0,0-5% gain=1, loss of bodyweight=2. Hair was normal (0) or dull (1); micewere lively (0) or apathetic (1). Stools were normal (0), semiliquid (1)or liquid (2). Rectal bleeding was given 1 point. Colon colour wasnormal (0) or red (1); distention was absent (0) or remarkable (1). Theserosal aspect was normal (0) or thickened (1). The groups depicted inFIG. 2 b are as follows: (A) healthy mice; (B) mice having TNBS-inducedcolitis treated with 5 mg/kg a compound disclosed in Table VIII from Day−1; (C) mice having TNBS-induced colitis treated with 5 mg/kg a compounddisclosed in Table VIII from Day +2; and (D) mice having TNBS-inducedcolitis receiving only vehicle.

See Cooper H S et al. “Clinicopathologic study of dextran sulfate sodiumexperimental murine colitis.” Lab Invest. 1993 August; 69(2):238-249.

FIG. 2 c shows the mesenteric lymph node (MLN) total leukocyte count foranimals receiving vehicle (A), TNBS induced colitis receiving onlyethanol vehicle (B), animals without TNBS induced colitis receiving 10mg/kg a compound disclosed in Table VIII (C); and animals havingTNSB-induced colitis and receiving 10 mg/kg a compound disclosed inTable VIII (D). As can be seen from these data, the animals receiving atreatment with a compound disclosed in Table VIII had a lower leukocytecount than animals with induced colitis receiving no drug.

FIG. 3 depicts the change in hematocrit levels for the various groups inthis study. Group A (healthy control) was not subjected to TNSB-inducedcolitis and only received a pre-treatment vehicle; Group B was subjectedto TNSB-induced colitis and only received a pre-treatment with vehicle;Group C was not subjected to TNSB-induced colitis but received apre-treatment of 5 mg/kg of a compound disclosed in Table VIII; Group Dwas subjected to TNSB-induced colitis and received a pre-treatment with0.3 mg/kg of a compound disclosed in Table VIII; Group E was subjectedto TNSB-induced colitis and received a pre-treatment with 1 mg/kg of acompound disclosed in Table VIII; and Group F was subjected toTNSB-induced colitis and received a pre-treatment with 5 mg/kg of acompound disclosed in Table VIII. As evidenced by these data, foranimals pre-treated with a compound disclosed in Table VIII there was nochange in hematocrit levels.

Xenograft Model: Mouse Colon 26 Carcinoma

Nude mice (Harlan Sprague Dawley, Inc., Indianapolis Ind.) wereinoculated subcutaneously in the right flank with 0.1 mL of a 0.9% NaClmixture containing a suspension of Mouse Colon 26 tumor cells (approx.1×10⁶ cells/mouse). Nine days following inoculation, the resultingtumors were measured using vernier calipers and tumor weight wascalculated using the formula:

${{Tumor}\mspace{14mu} {weight}\mspace{14mu} ({mg})} = \frac{\left. {{width}\mspace{14mu} ({mm})^{2} \times {length}\mspace{14mu} {mm}} \right)}{2}$

wherein the width can be taken as the smallest diameter and the lengththe largest diameter of the tumor. Twenty-four mice having tumors in therange of 75-144 mg were then selected. The mice were randomized intothree groups of eight mice each. The body weight of each animal was attaken when the mice were pair-matched on day one and recorded. Bodyweights were then taken twice weekly thereafter in conjunction withtumor measurements. See Britten C. D. et al., “Enhanced antitumoractivity of 6-hydroxymethyl-acylfulvene in combination with irinotecanand 5-fluorouracil in the HT29 human colon tumor xenograft model.”Cancer Res 1999; 59:1049-53, incorporated by reference herein in itsentirety.

Beginning on Day 1, 5-fluorouracil (5-FU) was administered intravenouslyonce daily for five days to each animal (Groups 1-3). Starting on Day 2,a compound disclosed in Table VIII was administered subcutaneously everyother day for 3 doses (Days 2, 4, and 6) at doses of either 5 mg/kg(Group 2) or 10 mg/kg (Group 3). The study terminated on Day 27 when thecontrol group tumor weight reached an average of 1926.9 mg. The micewere sacrificed and the tumors were collected from all mice. All animalssurvived the full course of this study. The actual weight of each tumorwas recorded. Table IX below shows the results of this study.

TABLE IX Dose Tumor Growth MeanTumor Group Drug (mg/kg) Route Tumor Wgt.Inhibition shrinkage 1 5-FU 10 IV 1926.9 ± 284.9 — — 2 5-FU 10 IV 1398.0± 384.6 18.5 (7/8) 52.0 (1/8) inhibitor* 5 SC 3 5-FU 10 IV 1118.2 ±378.9 24.3 (6/8) 87.5 (1/8) inhibitor* 10 SC *The inhibitor is acompound disclosed in Table VIII

As evidenced in Table IX overall tumor weight was significantly reducedin both groups receiving a compound disclosed in Table VIII incombination with 5-fluorouracil than Group 1 which received5-fluorouracil alone. Mean tumor shrinkage for animals in Group 3 was87% with one animal having complete shrinkage of the tumor.

Kits

Also disclosed are kits comprising the HIF-1α prolyl hydroxylaseinhibitors be delivered into a human or a mammal suffering from ordiagnosed with one or more diseases or conditions affecting intestinalepithelial tissue, inter alia, Crohn's disease, ulcerative colitis,collagenous colitis, lymphocytic colitis, ischemic colitis, diversioncolitis, Behcet's syndrome, and indeterminate colitis. The kits cancomprise one or more packaged unit doses of a composition comprising oneor more HIF-1α prolyl hydroxylase inhibitors to be delivered into ahuman or mammal. The units dosage ampules or multidose containers, inwhich the HIF-1α prolyl hydroxylase inhibitors to be delivered arepackaged prior to use, can comprise an hermetically sealed containerenclosing an amount of polynucleotide or solution containing a substancesuitable for a pharmaceutically effective dose thereof, or multiples ofan effective dose. The HIF-1α prolyl hydroxylase inhibitor can bepackaged as a sterile formulation, and the hermetically sealed containeris designed to preserve sterility of the formulation until use.

The disclosed HIF-1α prolyl hydroxylase inhibitors can also be presentin liquids, emulsions, or suspensions for delivery of active therapeuticagents in aerosol form to cavities of the body such as the nose, throat,or bronchial passages. The ratio of HIF-1α prolyl hydroxylase inhibitorsto the other compounding agents in these preparations will vary as thedosage form requires.

Depending on the intended mode of administration, the pharmaceuticalcompositions can be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, lotions, creams, gels, or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include, as noted above, aneffective amount of the HIF-1α prolyl hydroxylase inhibitor incombination with a pharmaceutically acceptable carrier and, in addition,can include other medicinal agents, pharmaceutical agents, carriers,adjuvants, diluents, etc.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc., an active compound as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered can also contain minor amounts of nontoxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, etc. Actualmethods of preparing such dosage forms are known, or will be apparent,to those skilled in this art; for example see Remington's PharmaceuticalSciences, referenced above.

Parental administration, if used, is generally characterized byinjection. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. A morerecently revised approach for parental administration involves use of aslow release or sustained release system, such that a constant level ofdosage is maintained. See, e.g., U.S. Pat. No. 3,710,795, which isincorporated by reference herein.

When the HIF-1α prolyl hydroxylase inhibitors are to be delivered into amammal, the mammal can be a non-human primate, horse, pig, rabbit, dog,sheep, goat, cow, cat, guinea pig or rodent. The terms human and mammaldo not denote a particular age or sex. Thus, adult and newborn subjects,as well as fetuses, whether male or female, are intended to be covered.A patient, subject, human or mammal refers to a subject afflicted with adisease or disorder. The term “patient” includes human and veterinarysubjects.

While particular embodiments of the present disclosure have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the disclosure. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this disclosure

1. A method for treating a subject with an inflammatory epithelialdisease, comprising administering to a subject an effective amount ofone or more compounds having the formula:

wherein L is chosen from CH₂ or SO₂; R represents from 0 to 5substitutions for hydrogen; the index n is an integer from 0 to 5; R¹and R² are each independently chosen from: i) hydrogen; ii) substitutedor unsubstituted C₁-C₁₀ linear, branched, or cyclic alkyl; iii)substituted or unsubstituted C₂-C₁₀ linear, branched, or cyclic alkenyl;iv) substituted or unsubstituted C₂-C₁₀ linear or branched alkynyl; v)substituted or unsubstituted C₆ or C₁₀ aryl; vi) substituted orunsubstituted C₁-C₉ heterocyclic; vii) substituted or unsubstitutedC₁-C₉ heteroaryl; or viii) R¹ and R² can be taken together to form asubstituted or unsubstituted heterocyclic or substituted orunsubstituted heteroaryl ring having from form 2 to 20 carbon atoms andfrom 1 to 7 heteroatoms; or a pharmaceutically acceptable salt thereof.2. The method according to claim 1, wherein the one or more compoundsare in the form of a pharmaceutically acceptable salt chosen fromhydrochloride salt, hydrogen sulfate salt, sulfate salt,p-toluenesulfonyl salt, methanesulfonyl salt and mixtures thereof. 3.The method according to claim 1, wherein the inflammatory epithelialdisease is a disease affecting intestinal epithelial tissue.
 4. Themethod according to claim 3, wherein the disease is Crohn's disease. 5.The method according to claim 3, wherein the disease is ulcerativecolitis.
 6. The method according to claim 3, wherein the disease iscollagenous colitis.
 7. The method according to claim 3, wherein thedisease is lymphocytic colitis.
 8. The method according to claim 3,wherein the disease is ischemic colitis.
 9. The method according toclaim 3, wherein the disease is diversion colitis.
 10. The methodaccording to claim 3, wherein the disease is Behcet's syndrome.
 11. Themethod according to claim 3, wherein the disease is indeterminatecolitis.
 12. The method according to claim 1, wherein the inflammatoryepithelial disease is chosen from a disease affecting the respiratorytract, mucosa, skin, GI tract, lining of major organs and endocrineglands, vascular tissue, and combinations thereof.
 13. The methodaccording to claim 1, wherein L is CH₂.
 14. The method according toclaim 1, wherein L is SO₂.
 15. The method according to claim 1, whereineach R is a substitution for hydrogen independently chosen from: i)substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂cyclic alkyl; ii) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂branched, or C₃-C₁₂ cyclic alkenyl; iii) substituted or unsubstitutedC₂-C₁₂ linear or C₃-C₁₂ branched alkynyl; iv) C₆ or C₁₀ substituted orunsubstituted aryl; v) C₁-C₉ substituted or unsubstituted heterocyclic;vi) C₁-C₁₁ substituted or unsubstituted heteroaryl; vii) halogen; viii)—[C(R^(23a))(R^(23b))]_(x)R¹⁰; R¹⁰ is chosen from: a) —H; b) substitutedor unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl;c) C₆ or C₁₀ substituted or unsubstituted aryl or alkylenearyl; d) C₁-C₉substituted or unsubstituted heterocyclic; e) C₁-C₁₁ substituted orunsubstituted heteroaryl; ix)—[C(R^(23a))(R^(23b))]_(x)N(R^(11a))(R^(11b)); R^(11a) and R^(11b) areeach independently chosen from: a) —H; b) —OR¹²; R¹² is hydrogen orC₁-C4 linear alkyl; c) substituted or unsubstituted C₁-C₁₂ linear,C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl; d) C₆ or C₁₀ substituted orunsubstituted aryl; e) C₁-C₉ substituted or unsubstituted heterocyclic;f) C₁-C₁₁ substituted or unsubstituted heteroaryl; or g) R^(11a) andR^(11b) can be taken together to form a substituted or unsubstitutedring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms chosenfrom oxygen, nitrogen, and sulfur; x) —[C(R^(23a))(R^(23b))]_(x)C(O)R¹³;R¹³ is: a) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,or C₃-C₁₂ cyclic alkyl; b) —OR¹⁴; R¹⁴ is hydrogen, substituted orunsubstituted C₁-C₄ linear alkyl, C₆ or C₁₀ substituted or unsubstitutedaryl, C₁-C₉ substituted or unsubstituted heterocyclic, C₁-C₁₁substituted or unsubstituted heteroaryl; c) —N(R^(15a))(R^(15b));R^(15a) and R^(15b) are each independently hydrogen, substituted orunsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl; C₆or C₁₀ substituted or unsubstituted aryl; C₁-C₉ substituted orunsubstituted heterocyclic; C₁-C₁₁ substituted or unsubstitutedheteroaryl; or R^(15a) and R^(15b) can be taken together to form asubstituted or unsubstituted ring having from 3 to 10 carbon atoms andfrom 0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur; xi)—[C(R^(23a))(R^(23b))]_(x)OC(O)R¹⁶; R¹⁶ is: a) substituted orunsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl; b)—N(R^(17a))(R^(17b)); R^(17a) and R^(17b) are each independentlyhydrogen, substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,or C₃-C₁₂ cyclic alkyl; C₆ or C₁₀ substituted or unsubstituted aryl;C₁-C₉ substituted or unsubstituted heterocyclic; C₁-C₁₁ substituted orunsubstituted heteroaryl; or R^(17a) and R^(17b) can be taken togetherto form a substituted or unsubstituted ring having from 3 to 10 carbonatoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen, andsulfur; xii) —[C(R^(23a))(R^(23b))]_(x)NR¹⁸C(O)R¹⁹; R¹⁸ is: a) —H; or b)substituted or unsubstituted C₁-C4 linear, C₃-C₄ branched, or C₃-C₄cyclic alkyl; R¹⁹ is: a) substituted or unsubstituted C₁-C₁₂ linear,C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl; b) —N(R^(20a))(R^(20b)); R²⁰and R^(20b) are each independently hydrogen, substituted orunsubstituted C₁-C₄ linear or C₂-C₄ branched alkyl; C₆ or C₁₀substituted or unsubstituted aryl; C₁-C₉ substituted or unsubstitutedheterocyclic; C₁-C₁₁ substituted or unsubstituted heteroaryl; or R^(20a)and R^(20b) can be taken together to form a substituted or unsubstitutedring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms chosenfrom oxygen, nitrogen, and sulfur; xiii) —[C(R^(23a))(R^(23b))]_(x)CN;xiv) —[C(R^(23a))(R^(23b))]_(x)NO₂; xv) —[C(R^(23a))(R^(23b))]_(x)R²¹;R²¹ is C₁-C₁₀ linear, branched, or cyclic alkyl substituted by from 1 to21 halogen atoms chosen from —F, —Cl, —Br, or —I; xvi)—[C(R^(23a))(R^(23b))]_(x)SO₂R²²; R²² is hydrogen, hydroxyl, substitutedor unsubstituted C₁-C₄ linear or C₂-C₄ branched alkyl; substituted orunsubstituted C₆, C₁₀, or C₁₄ aryl; C₇-C₁₅ alkylenearyl; C₁-C₉substituted or unsubstituted heterocyclic; or C₁-C₁₁ substituted orunsubstituted heteroaryl; R^(23a) and R^(23b) are each independentlyhydrogen or C₁-C₄ alkyl; and the index x is an integer from 0 to
 5. 16.The method according to claim 1, wherein R¹ and R² are taken together toform a 5-member substituted or unsubstituted C₁-C₄ heterocyclic or asubstituted or unsubstituted C₁-C₄ heteroaryl ring.
 17. The methodaccording to claim 16, wherein R¹ and R² are taken together to form aring having the formula:


18. The method according to claim 1, wherein R¹ and R² are takentogether to form a substituted or unsubstituted C₄-C₁₁ heterocyclic or asubstituted or unsubstituted C₄-C₁₁ heteroaryl ring.
 19. The methodaccording to claim 18, wherein R¹ and R² are taken together to form aring having the formula:


20. The method according to claim 1, wherein R¹ and R² are takentogether to form a ring chosen from pyrrolidin-1-yl,3-hydroxypyrrolidin-1-yl, 2-(pyridin-2-yl)pyrrolidin-1-yl,2-methylcarboxypyrrolidin-1-yl, 2-(methoxymethyl)pyrrolidin-1-yl,thiazolidin-3-yl, 1H-imidazol-1-yl, piperidin-1-yl,4-benzylpiperidin-1-yl, 1,4′-bipiperidinyl-1′-yl, piperazin-1-yl,4-benzylpiperazin-1-yl, 4-(2-methoxyphenyl)-piperazin-1-ylmethyl,4-(6-chloropyridazin-3-yl)piperazin-1-yl,1,4-dioxa-8-azaspiro[4,5]dec-8-yl, morpholin-4-yl, thiomorpholin-4-yl,azepan-1-yl, azocan-1-yl, and 3,4-dihydroquinolin-1(2H)-yl.
 21. Themethod according to claim 1, wherein R² is hydrogen and R¹ is chosenfrom benzyl, 4-methoxybenzyl, 4-fluorobenzyl, 4-chlorobenzyl,4-methylbenzyl, 2-(pyridin-2-yl)ethyl, [1,3]dioxolan-2-ylmethyl,tetrahydrofuran-2-ylmethyl, 2-methoxyethyl,1-hydroxy-2-methylpropan-2-yl, pyridin-4-ylmethyl, furan-2-ylmethyl,2-(methylthio)ethyl, 1-phenylethyl, 3-imidazol-1-ylpropyl, cycloheptyl,4-methylcyclohexyl, 1-benzylpiperidin-4-yl, azepan-2-on-3-yl, and1-benzylpyrrolidin-3-yl.
 22. The method according to claim 1, whereinthe one or more compounds have the formula:

wherein Z is phenyl substituted with from 1 to 5 halogens chosen fromfluorine and chlorine; R⁴ is C₁-C₄ linear alkyl or C₃-C₄ branched alkyl;or a pharmaceutically acceptable salt thereof.
 23. The method accordingto claim 22, wherein R⁴ is methyl.
 24. The method according to claim 22,wherein R⁴ is ethyl.
 25. The method according to claim 22, wherein R⁴ istert-butyl.
 26. The method according to claim 22, wherein Z is4-chlorophenyl.
 27. The method according to claim 22, wherein Z ischosen from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl,3-fluorophenyl, or 4-fluorophenyl.
 28. The method according to claim 22,wherein Z is chosen from 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, and 2,6-dichlorophenyl.
 29. Themethod according to claim 1, wherein the one or more compounds istert-butyl4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylateor a pharmaceutically acceptable salt chosen from hydrochloride salt,hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt,methanesulfonyl salt and mixtures thereof.
 30. The method according toclaim 1, wherein the one or more compounds is chosen from: Methyl4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Methyl4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Methyl4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Ethyl4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Ethyl4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Ethyl4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;tert-Butyl4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;tert-Butyl4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Methyl4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Methyl4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Methyl4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Ethyl4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Ethyl4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;Ethyl4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;tert-Butyl4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;tert-Butyl4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;and tert-Butyl4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate.31. A composition for treating a subject with an inflammatory epithelialdisease, comprising a) an effective amount of one or more compoundshaving the formula:

wherein L is chosen from CH₂ or SO₂; R represents from 0 to 5substitutions for hydrogen; the index n is an integer from 0 to 5; R¹and R² are each independently chosen from: i) hydrogen; ii) substitutedor unsubstituted C₁-C₁₀ linear, branched, or cyclic alkyl; iii)substituted or unsubstituted C₂-C₁₀ linear, branched, or cyclic alkenyl;iv) substituted or unsubstituted C₂-C₁₀ linear or branched alkynyl; v)substituted or unsubstituted C₆ or C₁₀ aryl; vi) substituted orunsubstituted C₁-C₉ heterocyclic; vii) substituted or unsubstitutedC₁-C₉ heteroaryl; or i) R¹ and R² can be taken together to form asubstituted or unsubstituted heterocyclic or substituted orunsubstituted heteroaryl ring having from form 2 to 20 carbon atoms andfrom 1 to 7 heteroatoms; R⁴ is C₁-C₄ linear or C₃-C₄ branched alkyl; ora pharmaceutically acceptable salt thereof; and b) one or moreexcipients.
 32. The composition according to claim 32, wherein the oneor more compounds are in the form of a pharmaceutically acceptable saltchosen from hydrochloride salt, hydrogen sulfate salt, sulfate salt,p-toluenesulfonyl salt, methanesulfonyl salt and mixtures thereof. 33.The composition according to claim 32, wherein the one or more compoundshave the formula:

wherein Z is phenyl substituted with from 1 to 5 halogens chosen fromfluorine and chlorine; R⁴ is C₁-C₄ linear alkyl or C₃-C₄ branched alkyl;or a pharmaceutically acceptable salt thereof.
 34. The compositionaccording to claim 32, wherein R⁴ is methyl.
 35. The compositionaccording to claim 32, wherein R⁴ is ethyl.
 36. The compositionaccording to claim 32, wherein R⁴ is tert-butyl.
 37. The compositionaccording to claim 32, wherein Z is 4-chlorophenyl.
 38. The compositionaccording to claim 32, wherein Z is chosen from 2-chlorophenyl,3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl. 39.The composition according to claim 32, wherein the one or more compoundsis tert-butyl4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylateor a pharmaceutically acceptable salt hydrochloride salt, hydrogensulfate salt, sulfate salt, p-toluenesulfonyl salt, methanesulfonyl saltand mixtures thereof.
 40. The composition according to claim 32, furthercomprising one or more chemotherapeutic compounds.
 41. The compositionaccording to claim 41, wherein the one or more chemotherapeuticcompounds are chosen from 6-hydroxymethylacylfulvene, cyclophosphamide,dacarbazine, carmustine, doxorubicin, and methotrexate.
 42. Thecomposition according to claim 32, wherein the inflammatory epithelialdisease is chosen from Crohn's disease, ulcerative colitis, collagenouscolitis, lymphocytic colitis, ischemic colitis, diversion colitis,Behcet's syndrome, and indeterminate colitis